a case study in muscle contraction

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12.4 Muscle Contraction

Created by CK-12 Foundation/Adapted by Christine Miller

Arm Wrestling

It’s obvious that a sport like arm wrestling (Figure 12.4.1) depends on muscle contractions. Arm wrestlers must contract muscles in their hands and arms, and keep  them contracted in order to resist the opposing force exerted by their opponent. The wrestler whose muscles can contract with greater force wins the match.

What Is a Muscle Contraction?

A  muscle contraction  is an increase in the tension or a decrease in the length of a muscle. Muscle tension is the force exerted by the muscle on a bone or other object. A muscle contraction is  isometric  if muscle tension changes, but muscle length remains the same. An example of isometric muscle contraction is holding a book in the same position. A muscle contraction is  isotonic  if muscle length changes, but muscle tension remains the same. An example of isotonic muscle contraction is raising a book by bending the arm at the elbow. The termination of a muscle contraction of either type occurs when the muscle relaxes and returns to its non-contracted tension or length.

To use our arm wrestling example, if both arm wrestlers have equal strength and they are pulling with all their might, but there is no movement, that is isometric muscle contraction.  However, as soon as one arm wrestler starts to win and is able to start pulling the opponents arm down, that is isotonic muscle contraction.

How a Skeletal Muscle Contraction Begins

Excluding reflexes, all skeletal muscle contractions occur as a result of conscious effort originating in the brain. The brain sends electrochemical signals through the somatic nervous system to motor neurons that innervate muscle fibres (to review how the brain and neurons function, see the chapter Nervous System) . A single motor neuron with multiple axon terminals is able to innervate multiple muscle fibres, thereby causing all of them to contract at the same time. The connection between a motor neuron axon terminal and a muscle fibre occurs at a site called a neuromuscular junction . This is a chemical synapse where a motor neuron transmits a signal to a muscle fibre to initiate a muscle contraction. The process by which a signal is transmitted at a neuromuscular junction is illustrated in Figure 12.4.2 below.

The sequence of events begins when an action potential is initiated in the cell body of a motor neuron , and the action potential is propagated along the neuron’s axon to the neuromuscular junction . Once the action potential reaches the end of the axon terminal, it causes the release of the neurotransmitter acetylcholine (ACh) from synaptic vesicles in the axon terminal. The ACh molecules diffuse across the synaptic cleft and bind to receptors on the muscle fibre, thereby initiating a muscle contraction.

Sliding Filament Theory of Muscle Contraction

Once the muscle fibre is stimulated by the motor neuron, actin and myosin protein filaments within the skeletal muscle fibre slide past each other to produce a contraction. The sliding filament theory is the most widely accepted explanation for how this occurs. According to this theory, muscle contraction is a cycle of molecular events in which thick myosin filaments repeatedly attach to and pull on thin actin filaments, so the filaments slide over one another, as illustrated in Figure 12.4.3. The actin filaments are attached to Z discs, each of which marks the end of a sarcomere . The sliding of the filaments pulls the Z discs of a sarcomere closer together, thus shortening the sarcomere. As this occurs, the muscle contracts.

Crossbridge Cycling

Crossbridge cycling is a sequence of molecular events that underlies the sliding filament theory . There are many projections from the thick myosin filaments, each of which consists of two myosin heads (you can see the projections and heads in Figures 12.4.3 and 12.4.4). Each myosin head has binding sites for ATP (or the products of ATP hydrolysis: ADP and Pi) and for actin. The thin actin filaments also have binding sites for the myosin heads. A crossbridge forms when a myosin head binds with an actin filament.

The process of crossbridge cycling is shown in the video “Muscle Contraction 3D” by 3DBiology (below), and in Figure 12.4.4. A crossbridge cycle begins when the myosin head binds to an actin filament. ADP and Pi are also bound to the myosin head at this stage. Next, a power stroke moves the actin filament inward toward the center of sarcomere, thereby shortening the sarcomere. At the end of the power stroke, ADP and Pi are released from the myosin head, leaving the myosin head attached just to the thin filament until another ATP binds to the myosin head. When ATP binds to the myosin head, it causes the myosin head to detach from the actin. ATP is once again split into ADP and Pi and the energy released is used to move the myosin head into a “cocked” position. Once in this position, the myosin head can bind to the actin filament again, and another crossbridge cycle begins.

Muscle Contraction 3D, 3DBiology, 2017.

Energy for Muscle Contraction

According to the sliding filament theory, ATP is needed to provide the energy for a muscle contraction. Where does this ATP come from? Actually, there are multiple potential sources, as illustrated in Figure 12.4.5 below.

• As you can see from the first diagram, some ATP is already available in a resting muscle. As a muscle contraction starts, this ATP is used up in just a few seconds. More ATP is generated from creatine phosphate , but this ATP is used up rapidly as well. It’s gone in another 15 seconds or so.
• Glucose from the blood and glycogen stored in muscle can then be used to make more ATP. Glycogen breaks down to form glucose, and each glucose molecule produces two molecules of ATP and two molecules of pyruvate. Pyruvate (as pyruvic acid) can be used in aerobic respiration if oxygen is available. Alternatively, pyruvate can be used in anaerobic respiration , if oxygen is not available. The latter produces lactic acid, which may contribute to muscle fatigue. Anaerobic respiration typically occurs only during strenuous exercise when so much ATP is needed that sufficient oxygen cannot be delivered to the muscle to keep up.
• Resting or moderately active muscles can get most of the ATP they need for contractions by aerobic respiration. This process takes place in the  mitochondria  of muscle cells. In the process, glucose and oxygen react to produce carbon dioxide, water, and many molecules of ATP.

Feature: Human Biology in the News

Basic research on muscle contraction, especially if it is interesting and hopeful, is often in the news, because muscle contractions are involved in so many different body processes and disorders, including heart failure and stroke.

• Heart   failure is a chronic condition in which cardiac muscle cells cannot contract forcefully enough to keep body cells adequately supplied with oxygen. According to a 2016 report by the Heart and Stroke Foundation of Canada , 600,000 Canadians are living with heart failure and each year, 50,000 new cases are diagnosed.  Heart failure costs the Canadian medical system more than $2.8 billion annually.  In 2016, researchers at the University of Texas Southwestern Medical Center identified a potential new target for the development of drugs to increase the strength of cardiac muscle contractions in patients with heart failure. The UT researchers found a previously unidentified protein involved in muscle contraction. The protein, which is very small, turns off the “brake” on the heart so it pumps blood more vigorously. At the molecular level, the protein affects the calcium-ion pump that controls muscle contraction. The scientists also found the same protein in slow-twitch skeletal muscle fibres. Interestingly, the protein is encoded by a stretch of mRNA that had been dismissed by scientists as non-coding RNA, commonly referred to as “junk” RNA. According to one of the researchers, “We dipped into the RNA ‘junk’ pile and came up with a hidden treasure.” This result is likely to lead to searches for additional treasures that might be hiding in the RNA junk pile.
• A  stroke occurs when a blood clot lodges in an artery in the brain and cuts off blood flow to part of the brain. Approximately 6% of deaths in Canada are due to stroke and while men and women experiences strokes almost equally, women are more likely to die from a stroke.  Damage from the clot associated with strokes would be reduced if the smooth muscles lining brain arteries relaxed following a stroke, because the arteries would dilate and allow greater blood flow to the brain. In a recent study undertaken at the Yale University School of Medicine, researchers determined that the muscles lining blood vessels in the brain actually contract after a stroke. This constricts the vessels, reduces blood flow to the brain, and appears to contribute to permanent brain damage. The hopeful takeaway of this finding is that it suggests a new target for stroke therapy.

12.4 Summary

• A muscle contraction is an increase in the tension or a decrease in the length of a muscle. A muscle contraction is isometric if muscle tension changes, but muscle length remains the same. It is isotonic if muscle length changes, but muscle tension remains the same.
• A skeletal muscle contraction begins with electrochemical stimulation of a muscle fibre by a motor neuron . This occurs at a chemical synapse called a neuromuscular junction . The neurotransmitter acetylcholine diffuses across the synaptic cleft and binds to receptors on the muscle fibre. This initiates a muscle contraction.
• Once stimulated, the protein filaments within the skeletal muscle fibre slide past each other to produce a contraction. The sliding filament theory is the most widely accepted explanation for how this occurs. According to this theory, thick myosin filaments repeatedly attach to and pull on thin actin filaments, thus shortening sarcomeres.
• Crossbridge cycling is a cycle of molecular events that underlies the sliding filament theory. Using energy in ATP, myosin heads repeatedly bind with and pull on actin filaments. This moves the actin filaments toward the center of a sarcomere, shortening the sarcomere and causing a muscle contraction.
• The ATP needed for a muscle contraction comes first from ATP already available in the cell, and more is generated from creatine phosphate. These sources are quickly used up. Glucose and glycogen can be broken down to form ATP and pyruvate. Pyruvate can then be used to produce ATP in aerobic respiration if oxygen is available, or it can be used in anaerobic respiration if oxygen is not available.

12.4 Review Questions

• What is a skeletal muscle contraction?
• Explain sliding filament theory and describe crossbridge cycling.
• If the acetylcholine receptors on muscle fibres were blocked by a drug, what do you think this would do to muscle contraction? Explain your answer.
• Explain how crossbridge cycling and sliding filament theory are related to each other.
• When does anaerobic respiration typically occur in human muscle cells?
• If there were no ATP available in a muscle, how would this affect crossbridge cycling? What would this do to muscle contraction?

12.4 Explore More

The Mechanism of Muscle Contraction: Sarcomeres, Action Potential, and the Neuromuscular Junction, Professor Dave Explains, 2019.

Aerobic vs Anaerobic Difference, Dorian Wilson, 2017.

Attributions

Figure 12.4.1

Armwrestling_Championships by Jnadler1 on Wikimedia Commons is used under a CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) license.

Figure 12.4.2

Motor_End_Plate_and_Innervation  by OpenStax on Wikimedia Commons is used under a CC BY 4.0 (https://creativecommons.org/licenses/by 4.0) license.

Figure 12.4.3

Sliding_Filament_Model_of_Muscle_Contraction  by OpenStax on Wikimedia Commons is used under a CC BY 4.0 (https://creativecommons.org/licenses/by 4.0) license.

Figure 12.4.4

Skeletal_Muscle_Contraction  by OpenStax on Wikimedia Commons is used under a CC BY 4.0 (https://creativecommons.org/licenses/by 4.0) license.

Figure 12.4.5

Muscle_Metabolism by OpenStax on Wikimedia Commons is used under a CC BY 4.0 (https://creativecommons.org/licenses/by 4.0) license.

3DBiology. (2017). Muscle contraction 3D. YouTube. https://www.youtube.com/watch?v=GrHsiHazpsw

Betts, J. G., Young, K.A., Wise, J.A., Johnson, E., Poe, B., Kruse, D.H., Korol, O., Johnson, J.E., Womble, M., DeSaix, P. (2016, May 27). Figure  10.6   Motor end-plate and innervation [digital image].  In Anatomy and Physiology (Section 10.2). OpenStax. https://openstax.org/books/anatomy-and-physiology/pages/10-2-skeletal-muscle

Betts, J. G., Young, K.A., Wise, J.A., Johnson, E., Poe, B., Kruse, D.H., Korol, O., Johnson, J.E., Womble, M., DeSaix, P. (2016, May 27). Figure 10.10 The sliding filament model of muscle contraction [digital image].  In Anatomy and Physiology (Section 10.3). OpenStax. https://openstax.org/books/anatomy-and-physiology/pages/10-3-muscle-fiber-contraction-and-relaxation

Betts, J. G., Young, K.A., Wise, J.A., Johnson, E., Poe, B., Kruse, D.H., Korol, O., Johnson, J.E., Womble, M., DeSaix, P. (2016, May 27). Figure 10.11 Skeletal muscle contraction [digital image].  In Anatomy and Physiology (Section 10.3). OpenStax. https://openstax.org/books/anatomy-and-physiology/pages/10-3-muscle-fiber-contraction-and-relaxation

Betts, J. G., Young, K.A., Wise, J.A., Johnson, E., Poe, B., Kruse, D.H., Korol, O., Johnson, J.E., Womble, M., DeSaix, P. (2016, May 27). Figure 10.12 Muscle metabolism [digital image].  In Anatomy and Physiology (Section 10.3). OpenStax. https://openstax.org/books/anatomy-and-physiology/pages/10-3-muscle-fiber-contraction-and-relaxation

Dorian Wilson. (2017, March 8). Aerobic vs anaerobic difference. YouTube.  https://www.youtube.com/watch?v=8Y_FdjI2v4I&feature=youtu.be

Heart and Stroke Foundation. (2016). 2016 Report on the health of Canadians: The burden of heart failure. https://www.heartandstroke.ca/-/media/pdf-files/canada/2017-heart-month/heartandstroke-reportonhealth-2016.ashx?la=en

Hill, R. A., Tong, L., Yuan, P., Murikinati, S., Gupta, S., & Grutzendler, J. (2015). Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron , 87 (1), 95–110. https://doi.org/10.1016/j.neuron.2015.06.001

UTSouthwestern Newsroom. (2016, January 14). Researchers find a small protein that plays a big role in heart muscle contraction [online article]. https://www.utsouthwestern.edu/newsroom/articles/year-2016/dworf-protein-olson.html

What we do. (n.d.). Heart and Stroke Foundation of Canada. https://www.heartandstroke.ca/what-we-do

Increase in the tension or decrease in the length of a muscle that occurs when muscle fibers receive stimulation from the nervous system.

Referring to a muscle contraction in which muscle tension increases but muscle length remains the same.

Referring to a muscle contraction in which muscle length decreases but muscle tension remains the same.

A division of the peripheral nervous system that controls voluntary activities.

A type of neuron that carries nerve impulses from the central nervous system to muscles and glands; also called efferent neuron.

A chemical synapse where a motor neuron transmits a signal to a muscle fiber to initiate a muscle contraction.

Reversal of electrical charge across the membrane of a resting neuron that travels down the axon of the neuron as a nerve impulse.

An organic chemical that functions in the brain and body of many types of animals (and humans) as a neurotransmitter—a chemical message released by nerve cells to send signals to other cells, such as neurons, muscle cells and gland cells.

A space that separates two neurons. It forms a junction between two or more neurons and helps nerve impulse pass from one neuron to the other.

A protein on a cell membrane or inside of a cell that binds with a hormone, neurotransmitter, or other chemical signal to produce a response.

A protein that forms (together with myosin) the contractile filaments of muscle cells, and is also involved in motion in other types of cells.

A fibrous protein that forms (together with actin) the contractile filaments of muscle cells and is also involved in motion in other types of cells.

A theory that explains muscle contraction by the sliding of myosin filaments over actin filaments within muscle fibers.

The basic functional unit of skeletal and cardiac muscles, containing actin and myosin protein filaments that slide over one another to produce a shortening of the sarcomere resulting in a muscle contraction.

A sequence of molecular events that forms crossbridges between myosin and actin filaments in muscle fibers, allowing for muscle contraction. "Heads" on the myosin filaments essentially form a connection with specific locations on the actin, and then the head bends in order to pull the myosin strand along the actin to shorten the sarcomere.

A complex organic chemical that provides energy to drive many processes in living cells, e.g. muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all forms of life, ATP is often referred to as the "molecular unit of currency" of intracellular energy transfer.

An organic compound of creatine and phosphate, also known as phosphocreatine, which when hydrolyzed (split apart) releases energy for muscle contraction.

Glucose (also called dextrose) is a simple sugar with the molecular formula C6H12O6. Glucose is the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using energy from sunlight.

A multi-branched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria.

The process of producing cellular energy involving oxygen. Cells break down food in the mitochondria in a long, multi-step process that produces roughly 36 ATP. The first step in is glycolysis, the second is the Krebs cycle and the third is the electron transport system.

Respiration using electron acceptors other than molecular oxygen. Although oxygen is not the final electron acceptor, the process still uses a respiratory electron transport chain.

A double-membrane-bound organelle found in most eukaryotic organisms. Mitochondria convert oxygen and nutrients into adenosine triphosphate (ATP). ATP is the chemical energy "currency" of the cell that powers the cell's metabolic activities.

A term used to describe a heart that cannot keep up with its workload. The body may not get the oxygen it needs. Heart failure is a serious condition, and usually there's no cure.

A cerebrovascular accident in which a broken artery or blood clot results in lack of blood flow to part of the brain, causing death of brain cells.

A type of chemical that transmits signals from the axon of a neuron to another cell across a synapse.

Human Biology Copyright © 2020 by Christine Miller is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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All or Nothing: A case study in muscle contraction

ese four undergraduate students contributed equally to the creation of this case study and are listed in alphabetical order. Case copyright held by the National Center for Case Study Teaching in Science, University at Buff alo, State University of New York. Originally published September 29, 2016. Please see our usage guidelines, which outline our policy concerning permissible reproduction of this work. Photograph by Victoria Garcia, Open Stax, <https://cnx.org/contents/[email protected]:mU03zyTM@2/Interactions-of-Skeletal-Muscl>, cc by 4.0. Part I – The Tour

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Skeletal muscle: A review of molecular structure and function, in health and disease

Kavitha mukund.

1 Department of Bioengineering, University of California, San Diego California

Shankar Subramaniam

2 Department of Bioengineering, Bioinformatics & Systems Biology, University of California, San Diego California

3 Department of Computer Science and Engineering, University of California, San Diego California

4 Department of Cellular and Molecular Medicine and Nanoengineering, University of California, San Diego California

Associated Data

Supplementary Table 2 . A list of myopathies with known genetic associations in muscle genes mentioned in the manuscript is presented. Inflammatory, idiopathic myopathies or myopathies resulting as a consequence of other diseases are not listed in the table.

Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The “omics” revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross‐talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems‐level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis.

This article is categorized under:

• Physiology > Mammalian Physiology in Health and Disease
• Developmental Biology > Developmental Processes in Health and Disease
• Models of Systems Properties and Processes > Cellular Models

The current review focuses on molecular structure and function of the various components of muscle physiology. Within each component, we highlight the necessary molecular mechanisms and cross‐talk critical for defining the state of muscle health. We also highlight instances of aberrant molecular mechanisms underlying disease.

1. INTRODUCTION

Striated muscle is composed of two major muscle types—skeletal and cardiac. While the cardiac (heart) muscle functionally represents a set of self‐stimulating, non‐fatiguing muscle cells with an intermediate energy requirement, skeletal muscle represents a set of innervated, voluntary muscle cells that exhibit fatigue with high energy requirements (e.g., muscles of the thigh or forearm). A cursory glance at the cellular structure and molecular cross‐talk allows us to appreciate the complexity in composition, structure and function of striated muscle, designed to accomplish the task of generating contraction, force and movement. Briefly, skeletal muscle is a highly organized tissue containing several bundles of muscle fiber (myofibers). Each myofiber (containing several myofibrils), represents a muscle cell with its basic cellular unit called the sarcomere. Bundles of myofibers form the fascicles, and bundles of fascicles form the muscle tissue, with each layer successively encapsulated by the extracellular matrix (ECM; Lieber, 2009 ) and supported by the cytoskeletal networks. Skeletal muscle is highly vascularized and innervated, and embedded with components of the metabolic and regulatory machinery, supporting efficient energy production and cellular homeostasis (Figure ​ (Figure1). 1 ). Precisely coordinated activity between each of these components is essential for shaping the state of muscular health and associated motor activity. Any perturbations (e.g., genetic or environmental) to this coordination, result in loss of muscle health and function, typically characterized by muscle fiber loss, reduced motor output and in some cases death.

Schematic representation of skeletal muscle fiber—a single mature muscle fiber is shown here as a bundle of myofibrils, encased by the sarcolemma. The sarcoplasmic reticulum enmeshes fibrils with transverse (T) tubules intersecting them. Bundles of myofibers form fascicles, which further group together to form the muscle tissue. Satellite cells reside along the host muscle fiber, directly above the sarcolemma under the basal lamina of muscle and in proximity of myonuclei. Innervating nerve fibers and local capillaries extend along the length of the muscle fiber. Each layer is successively encased by the extracellular matrix, not shown here

Over the decades, reviews in skeletal muscle research have focused extensively on specific aspects of muscle structure, or function. Our current review focuses on providing a more holistic picture of the various interacting components within skeletal muscle. In this review, we emphasize the idea of viewing the muscle as a biomechanical device requiring the coordination between several factors (or components) both intrinsic (e.g., genetic) and extrinsic (e.g., environmental stressors, circulatory factors, etc.) essential for normal muscle function. Within each of these components, we highlight the necessary molecular cross‐talk critical for defining its state. We also highlight instances of aberrant molecular mechanisms leading to disease, thus, bridging muscle research at genomic, molecular and mechanistic level, in health and disease (Figure ​ (Figure2 2 ).

Components of muscle structure and function—a schematic representation of the various functional components necessary for or arising as a consequence of muscle function, in health and disease. The structure and function of each of these units are discussed in this current review. The arrows identify a one‐word description for each of the units and their role in governing normal muscle function

This review begins with a focus on muscle tissue “development and regeneration”, outlining the embryological development of muscle, and the role for specific muscle regulatory factors in growth and development (Section 2 ). We also review satellite cell quiescence and activation that govern muscle regeneration and repair (Section 3 ). The “structural and functional” aspects of muscle, starting with the three most basic units that drive skeletal muscle contraction, namely (a) Neuromuscular junction (NMJ) which serves as a junction between nerve and muscle; (b) Machinery involved in excitation–contraction coupling (ECC), which is the process of transduction of electric impulses from nerve to muscle, required to initiate mechanical contraction; and (c) Sarcomere, the contractile apparatus required for force generation are discussed in Sections 4 – 6 . Different muscle fiber types and the effect of exercise on fiber‐type remodeling are also presented. We next discuss the ECM which encapsulates the muscle, protecting it (Section 7 ), and the cytoskeleton, which is necessary for mechanical support, and capable of sustaining muscle's rapid contraction and relaxation cycles (Section 8 ). We discuss the pathophysiological changes arising in muscle as a response to triggers (such as inflammation, oxidative stress, exercise), specifically, the impact on structural and functional integrity of the muscle, such as fibrosis, hypertrophy and atrophy in Sections 7 and 9 . Stress signaling (e.g., due to disease or injury) initiates a host of protective responses including inflammation and oxidative stress and are discussed in Section 10 . Carbohydrate metabolism serves as the major energy source required for muscle function. We discuss the basic bioenergetics pathways associated with energy metabolism (glucose and fat) in Section 11 , along with a brief introduction to the effect of exercise on metabolism. The dynamics of interaction between molecular actors of immunity and metabolism (immunometabolism) has been recently identified as vital to maintaining the health of skeletal muscle and is also discussed. The vasculature necessary for oxygenation required to sustain muscle is reviewed in Section 12 , with a special emphasis on vascular endothelial growth factors (VEGFs). Through the sections, we highlight and emphasize molecular perturbations and clinical manifestations of relevant diseases affecting muscle (italicized in text). Finally, in Section 13 , we summarize and highlight common molecular mechanisms underlying a spectrum of muscle disorders, identified in our work previously, and using a network theoretic approach.

Research in the past decade has increasingly acknowledged the contribution of noncoding components (e.g., long noncoding RNAs [lncRNAs], small open reading frames [smORFs]) to muscle development and function (Anderson et al., 2015 ; Andrews & Rothnagel, 2014 ; Fatica & Bozzoni, 2014 ; Gonçalves & Armand, 2017 ; Lim et al., 2018 ; Nelson et al., 2016 ; Nie, Deng, Liu, & Wang, 2015 ). However, it is beyond the scope of our current review and discussed only cursorily. The complexity in structure and function for each of the 13 units discussed here are immense, with several years of dedicated study by researchers. In this current review, we present a basic list of cellular components and molecular mechanisms for each unit, introducing the reader to the breadth of muscle research. In many instances, we use the more widely used names or symbols for several molecular markers within this review for improved readability. We provide their official gene symbol in Supplementary Table 1 for accuracy. The interested reader is directed to outstanding papers, of research and reviews, for in‐depth discussions of relevant mechanisms and concepts, within the individual topics discussed here.

2. MUSCLE EMBRYOLOGICAL DEVELOPMENT AND THE ROLE FOR MUSCLE REGULATORY FACTORS

The positions and identities of cells that will form the three germ layers (ectoderm, mesoderm, and endoderm) are determined early in gestation (S. J. Arnold & Robertson, 2009 ). The mesoderm is anatomically separated into paraxial, intermediate, and lateral mesoderm, based on the position from the midline/neural tube. Lineage tracing and fate‐mapping experiments have identified that embryonically, body skeletal muscle is derived from mesodermal precursor cells originating from the myotome, a somite‐derived lineage (Tajbakhsh & Cossu, 1997 ). Somites are bilaterally paired epithelial clusters that are formed by epithelialization of the paraxial mesoderm concomitant with segmentation. The processes of somite formation, segmentation and myogenesis are closely regulated by expression of genes involved directly or indirectly with WNT (von Maltzahn, Chang, Bentzinger, & Rudnicki, 2012 ), FGF (Pownall & Isaacs, 2010 ) and the inhibitory NOTCH (Buas & Kadesch, 2010 ) signaling pathways, in addition to the four myogenic regulatory factors (MRFs, MYOG1, MYOD, MRF4, and MYF5) (Bentzinger, Wang, & Rudnicki, 2012 ; Pownall, Gustafsson, & Emerson, 2002 ).

PAX3, a transcription factor, controls migration of muscle precursor cells by regulating LBX1 and cMET (Birchmeier & Brohmann, 2000 ). SIX1 and SIX4, two transcription factors are considered to be at the apex of the regulatory cascade that establishes the myogenic lineage of the precursor cells (Bentzinger et al., 2012 ; Grifone et al., 2005 ). Myoblasts activate MYF5 and MYOD1, two MRFs that control specification of head, epaxial, hypaxial and limb body muscle progenitors of the vertebrate embryo and mark a commitment to the muscle lineage. MYOD1 expression persists beyond differentiation, while MYF5 ceases during differentiation. Activation of a second wave of MRFs (MYOG and MRF4) induces terminal differentiation of myoblasts into myocytes that additionally express muscle‐specific genes such as the contractile proteins of the muscle (myosin, actin, etc.) and muscle creatine kinase. The mononucleated myocytes eventually fuse to form multinucleated, mature, contracting muscle fibers (Figure ​ (Figure3). 3 ). However, an understanding of specific molecular mechanisms controlling cell fusion of myocytes to mature myofibers is yet to be achieved. Recently, a minimal “two component program” for the induction of mammalian myocyte fusion comprising of Minion, an essential microprotein and Myomaker, a transmembrane protein (Gamage et al., 2017 ; Millay et al., 2013 ; Millay, Sutherland, Bassel‐Duby, & Olson, 2014 ), have been identified as sufficient for fusion (Q. Zhang, Vashisht, O'Rourke, et al., 2017 ). During the late phase of embryonic myogenesis, a distinct population of somite‐derived precursor cells remain in a quiescent undifferentiated state closely associated with myofibers (Lepper & Fan, 2010 ) and are called (adult) satellite cells (SCs). Many shared components including transcription factors and signaling molecules exist between embryonic myogenesis and muscle regeneration by SC activation in mature skeletal muscle (Tajbakhsh, 2009 ), as will be seen in the following section detailing SC quiescence, activation and muscle regeneration.

Expression of markers and pathways involved in stages of quiescence, activation and differentiation of satellite cells. During embryonic development, a portion of the muscle precursor cell population are incorporated into postnatal muscle as quiescent satellite cells which can transform again into muscle precursor cells (myogenic progenitor cells), upon activation. The major molecular markers and pathways that are necessary for transition of satellite cells from quiescent to a differentiated state are identified here. The markers/pathways that are upregulated are shown in green, downregulated in red

3. SATELLITE CELLS AND MUSCLE REGENERATION

Regeneration is one of the hallmarks of mature skeletal muscle tissue. Its ability to regenerate is governed significantly by the interaction between SCs (Scharner & Zammit, 2011 ) (SCs, unipotent muscle precursor cells) and its microenvironment (niche) (Lander, Kimble, Clevers, et al., 2012 ). Muscle regeneration is a highly orchestrated process, which involves activation and migration of SCs to the site of injury and their proliferation and differentiation into muscle fibers.

SCs represent a population of adult stem cells, mostly derived from PAX3 + /PAX7 + embryonic progenitor cells (Buckingham, 2007 ), and incorporated into growing fibers during postnatal muscle development. Anatomically, SCs appear wedged between basal lamina (BL), and the sarcolemma, sequestered in a particular microenvironment called the “niche,” within the adult skeletal muscle (Yin, Price, & Rudnicki, 2013 ). These cells are in a “quiescent”/hibernating state. The BL serves as a scaffold for SCs and functions to limit and orient their migration during injury (Sanes, 2003 ). BLs present a large number of binding sites for integrins‐α7/integrin‐β1, which anchor the actin cytoskeleton of SCs to the BL (Blanco‐Bose, Yao, Kramer, & Blau, 2001 ). This tethering also serves to relay extracellular mechanical cues (from myofibers) into intracellular chemical signals (within the SCs) (Boppart, Burkin, & Kaufman, 2006 ). The niche embedding the SCs is composed of both acellular and cellular components, including growth factors (GFs), ECM proteins, fibroadipogenic progenitors (FAPs), chemokines, and matrix metalloproteinases (MMPs). Beyond the immediate niche, local interstitial cells, motor neurons, vasculature and secreted factors (e.g., see Section 12.1 ), all have an ability to influence SC activity (Dumont, Wang, & Rudnicki, 2015 ; Yin et al., 2013 ).

The SC population is heterogeneous, differing in lineage potential, expression patterns, and myogenic differentiation potential (Kuang, Kuroda, Le Grand, & Rudnicki, 2007 ). The SC population is maintained uniformly, which however reduces in population density and efficacy with age (Almada & Wagers, 2016 ). Functional differences in regenerative potential exist between satellite stem cells (never expressed MYF5) and committed myogenic progenitor cells (that have expressed MYF5 at some point in development). Following transplantation, SCs preferentially repopulate the SC niche and contribute to long‐term muscle regeneration in a PAX7‐dependent manner (Günther et al., 2013 ).

3.1. Satellite cell quiescence

Quiescence defines a state of dormancy in adult stem cells, with quiescent SCs (QSCs) exhibiting an ability to rapidly activate, proliferate and differentiate into myofibers upon injury. The QSCs are characterized by the expression of definitive molecular markers, particularly PAX7, and a marked absence of two MRFs, MYOD1 and MYOG (Figure ​ (Figure4). 4 ). Activation of NOTCH (Bjornson et al., 2012 ) and WNT signaling is essential for maintaining quiescence in SCs by inhibiting MYOD1 expression and inducing PAX7 (Olguin & Olwin, 2004 ). Recent work has identified an alternative pathway for NOTCH activation involving FOXO3 in QSCs (Gopinath, Webb, Brunet, & Rando, 2014 ). Several other molecular markers regulating quiescence have been identified including cell cycle inhibitors such as p21, p27 (Fukada et al., 2007 ), and DACH1 (which inhibits cell cycle progression and regulates activity of pro‐myogenic SIX1 and SIX4) (Pallafacchina et al., 2010 ). Skeletal muscle‐specific TGFβ family member, myostatin, suppresses SC activation via induction of p21 (McCroskery, Thomas, Maxwell, Sharma, & Kambadur, 2003 ; Thomas et al., 2000 ). Retinoblastoma proteins (Carnac et al., 2000 ; Weinberg, 1995 ), and activated ID proteins (Benezra, Davis, Lockshon, Turner, & Weintraub, 1990 ) (particularly ID3; Kumar, Shadrach, Wagers, & Lassar, 2009 ) have also been identified as essential markers of QSCs. Activated CALCR, a calcitonin receptor, serves as both a spatial and temporal regulator of QSCs (Fukada et al., 2007 ; Yamaguchi et al., 2015 ). SPRY1, a tyrosine inhibitor kinase, is necessary for maintenance and re‐entry of PAX7 + SCs into quiescence (Shea, Xiang, LaPorta, et al., 2010 ). Additionally, integrin‐β1 and CXCR4, integrin‐α7 and CD34 are all definitive cell surface markers for QSCs in skeletal muscle, in vivo (Maesner, Almada, & Wagers, 2016 ). A detailed review of additional molecular markers, metabolic states, and mobility of QSCs is presented in Rocheteau, Vinet, and Chretien ( 2015 ).

Hierarchy of transcription factors regulating myogenic lineage. This figure represents the major transcription factors involved in muscle development and shows their temporal sequence of activation across various stages of myogenesis. Satellite stem cells expressing PAX7 derive from the PAX3/PAX7 expressing progenitors, whereas satellite myogenic cells additionally exhibit an activation of MYF5. Following activation and entrance into the cell cycle, stem cells express MYF5 and MYOD1. Activation of MYOG and MEF2C, with downregulation of MYF5 and later MYOD1 mark the start of terminal differentiation. Activation of MRF4 happens several days after the induction of differentiation, following a reduction in MYOG

3.2. Satellite cell activation, differentiation, and proliferation

In response to muscle injury, several environmental cues (niche) and chemical signals trigger activation of SCs, signaling the proliferation and differentiation of SCs to mature fibers, replacing damaged ones. Activated SCs (ASCs) are characterized by PAX7 and MRF expression (MYOD1, MYOG, and MYF5). The relative expression of MYOD1, MYOG, and MYF5 in PAX7 + cells and their temporal sequence regulates and maintains ASC proliferation (reviewed in detail in Yin et al., 2013 ; Figure ​ Figure4). 4 ). Terminal differentiation begins with downregulation of MYF5 and later MYOD1, and a concerted expression of MYOG, MEF2C, and MRF4 much later. Downstream targets of MYOD1 and MYOG (including MEF2s), further activate fiber type specific contractile and cytoskeletal genes (Cooper et al., 1999 ; Yin et al., 2013 ). Several mechanisms are suggested to play a role in the activation of MRFs and its downstream targets (Francetic & Li, 2011 ). For instance, MYF5 is induced via the methyltransferase CARM1's action on PAX7 and recruitment of histone acetyltransferases to the enhancers of MYF5 (Kawabe, Wang, McKinnell, Bedford, & Rudnicki, 2012 ). PAX3 also regulates early MYF5 expression via direct regulation of DMRT2 (Sato, Rocancourt, Marques, Thorsteinsdóttir, & Buckingham, 2010 ). SIX family of proteins (SIX1, SIX4) regulate MYOG expression, particularly, SIX4 repress MYOG, while SIX1 activate MYOG expression, thereby regulating proliferation and differentiation fates of ASCs (Yajima et al., 2010 ).

The migration to, and proliferation of SCs at the site of injury is driven by chemoattractants (released from the ECM or from the inflammatory cells), mostly, GFs such as VEGFs (see Section 12.1 ), fibroblast GFs, insulin GFs, and hepatocyte GFs, damage‐associated molecular patterns (Hindi & Kumar, 2016 ; Lotze et al., 2007 ), and cytokines (TNFα and TGFβ) released by resident cells and infiltrating inflammatory cells (Allen & Boxhorn, 1989 ; Christov et al., 2007 ; Y.‐P. Li, 2003 ; Sheehan & Allen, 1999 ; Tidball & Villalta, 2010 ). The JAK‐STAT pathway, activated by various cytokines, has been suggested to play a crucial role in early myogenic differentiation (K. Wang, Wang, Xiao, Wang, & Wu, 2008 ) and SC proliferation and differentiation (Doles & Olwin, 2014 ). More recent studies also demonstrate the requirement of Gαi2, the α‐subunit of the heterotrimeric G‐protein complex, for SC differentiation in a protein kinase C and histone deacetylase (HDAC)‐dependent manner (Minetti et al., 2014 ).

During regeneration, a portion of the ASC population has the capacity to return to quiescence to maintain the SC pool, essential for maintaining muscle integrity. STAT3 has been shown to regulate the self‐renewal potential of SCs (H. Zhu et al., 2016 ), in injured muscle, during muscle regeneration. STAT3 is also associated with SC proliferation in an IL‐6‐dependent manner upon injury (Toth et al., 2011 ). The local production of IL‐6 by skeletal muscle cells and stromal cells upon injury/exercise promotes SC activation, though the precise signaling mechanism of IL‐6‐dependent SC activation and proliferation, under various physiological states (e.g., injury, aging) is under much scrutiny (Belizário, Fontes‐Oliveira, Borges, Kashiabara, & Vannier, 2016 ; Brack & Muñoz‐Cánoves, 2015 ). p38MAPK serves as a powerful regulator of myogenesis via regulation of MRF activation (Lluís, Perdiguero, Nebreda, & Muñoz‐Cánoves, 2006 ) and stem cell renewal and quiescence (Segalés, Perdiguero, & Muñoz‐Cánoves, 2016 ). Fibroblast GF signaling serves as a potent activator of both STATs and p38MAPK in SCs (Pawlikowski, Orion Vogler, Gadek, & Olwin, 2017 ).

Mechanistic insights into the metabolic constraints for maintaining quiescence and transitioning to a proliferating/differentiating state are still in its infancy. Current research points to a switch from oxidative phosphorylation as energy source in quiescence to glycolysis in proliferating SCs (Koopman, Ly, & Ryall, 2014 ). The presence of an autophagic flux via the activation of SIRT1, a NAD + /NADH (nutrient) sensor, in QSCs is suggested as being required to meet the bioenergetics demands of the SC upon activation (Pardo & Boriek, 2011 ; Tang & Rando, 2014 ).

An understanding of posttranslational modifications and epigenetic control on SC quiescence, proliferation and differentiation states is gaining momentum and has been reviewed in detail in Segalés et al. ( 2016 ). They form an important mechanism for regulating the activation and activity of MRFs and subsequently of myogenesis (Giordani & Puri, 2013 ; Puri & Sartorelli, 2000 ; Saccone & Lorenzo, 2010 ).

Research in dystrophies have shown impacted activity of SCs which additionally undergo premature senescence (akin to sarcopenia) and a significant reduction in their population sizes, contribute to a reduction in muscle regenerative capacity (Heslop, Morgan, & Partridge, 2000 ; Jiang et al., 2014 ; Kudryashova, Kramerova, & Spencer, 2012 ; Yablonka‐Reuveni & Anderson, 2006 ). Efforts are underway to rejuvenate stem cells to mitigate the effects of stem‐cell aging on muscle regeneration (Bengal, Perdiguero, Serrano, & Muñoz‐Cánoves, 2017 ) with a possibility of offering therapeutic relief in chronic diseases such as the dystrophies.

In the following sections, we review the basic molecular structure of muscle tissue and the components that enable muscle function.

4. NEUROMUSCULAR JUNCTION

NMJ is the chemical synapse responsible for transmission of electric impulses from the innervating motor neuron to the innervated muscle fibers. The complexity and distribution of NMJs on the surface of muscle fibers differ greatly within and between muscle fibers in health and disease (Hall & Sanes, 1993 ; Hughes, Kusner, & Kaminski, 2006 ; Sanes & Lichtman, 1999 ). The NMJ comprises of three major regions: (a) the presynaptic region, comprising of the Schwann cell which envelops the nerve terminal containing the neurotransmitter; (b) the synaptic space lined by the basement membrane; and (c) the postsynaptic region containing the junctional sarcoplasm, and the postsynaptic membrane which contains receptors for the neurotransmitter (Figure ​ (Figure5 5 ).

A schematic representation of a neuromuscular junction (NMJ) and its main molecular actors—three specific regions define the NMJ: (a) the presynaptic motor nerve terminal where vesicles fuse with the terminal membrane to release acetylcholine (ACh) into the synaptic cleft. Calcium influx through the voltage‐gated Ca channels (VGCC) trigger vesicle fusion and release from the active zones (described in detail in Section 5 .1); (b) the synaptic space contains the basal lamina (BL, extra cellular matrix layer), and shows the presence of AChE‐ColQ (essential for the inactivation of ACh). ColQ binds MuSK and Perlecan necessary for stabilization of BL. MuSK enables AChR clustering via rapsyn (detailed in Section 5 .2); (c) postsynaptic organization of the skeletal muscle membrane include several folds with receptors for the diffusing ACh (AChRs) at the crest and voltage‐gated sodium channels (VGSC) in the troughs of the folds necessary for efficient neuromuscular transmission. The agrin‐Lrp4‐MuSK complex, present on the trough of the postsynaptic membrane is essential for the formation of the NMJ (described in detail in Section 5 .3). The entire structure is finally attached to the actin cytoskeleton (not shown here for simplicity)

4.1. Presynaptic region

Schwann cell envelops much of the nerve terminal at the NMJ, except the part that faces the postsynaptic membrane. The nerve terminal contains an abundance of synaptic vesicles (SVs), which function to store, release and uptake the neurotransmitter, acetylcholine (ACh) (Denker & Rizzoli, 2010 ; Rizzoli & Betz, 2005 ). SVs fuse to the presynaptic membrane at “active zones” initiating neuromuscular transmission (Nishimune, 2012 ). Active zones are visually dense zones, containing specialized proteins (such as Piccolo, Bassoon, and RIM1, interconnected by fibrils and embedded in a matrix), at the presynaptic membrane. Active zones are associated with vesicle docking and fusion, exocytosis, and vesicle recovery (Ackermann, Waites, & Garner, 2015 ). SVs are known to dock at active zones in highly definite patterns (Harlow, Ress, Stoschek, Marshall, & McMahan, 2001 ; Szule et al., 2012 ). Synapsin is suggested to anchor vesicles in reserve pools to the actin cytoskeleton, which are transported to active zones by myosin motors on actin tracks upon synaptic ingress of Ca 2+ via presynaptic P/Q type voltage‐gated calcium channels (VGCCs P/Q type; Cai & Sheng, 2009 ; Südhof, 2004 ). Rapid exocytosis from active zones is closely orchestrated by Ca 2+ and subsequently by the VGCC. Lambert–Eaton myasthenic syndrome, a rare autoimmune disease of the presynaptic membrane, manifests when IgG antibodies cross‐link VGCC, leading to a disruption of normal architecture and affecting active zone complexes (Fukunaga, Engel, Osame, & Lambert, 1982 ). The coupling mechanisms and modes of exocytosis of SVs are varied and are suggested to depend largely on muscle type and stimulus (Alabi & Tsien, 2013 ; L.‐G. Wu, Hamid, Shin, & Chiang, 2014 ).

The exocytotic machinery comprises mainly of the soluble NSF‐attachment protein receptor (SNARE) and SEC1/MUNC18‐like (SM) proteins, which bring vesicles in close proximity of the presynaptic membrane (reviewed in Südhof & Rizo, 2011 ). Formation of a SNARE complex (the SNARE pin) occurs in three steps: (a) Presynaptic membrane‐associated SNAP25 binds syntaxin‐1 forming a complex (t‐SNARE) at the presynaptic membrane. SM proteins (specifically MUNC18) binds to assembling SNARE complex via syntaxin‐1, and has been shown to be essential for SV fusion in vivo (Shen, Tareste, Paumet, Rothman, & Melia, 2007 ); (b) Synaptogamins serve as a sensor for presynaptic Ca 2+ and bind with the t‐SNARE, bringing the vesicle in close proximity to the presynaptic membrane (C. Wang, Bai, Chang, Chapman, & Jackson, 2006 ); (c) t‐SNARE engages vesicle‐associated VAMP/synaptobrevin to complete the formation of the SNARE complex. Complexins (CPLX1), that bind syntaxin‐1 with synaptobrevins, play a role in both repressing and activating SNARE‐dependent vesicle fusion, in conjunction with Ca 2+ activated synaptogamins (Maximov, Tang, Yang, Pang, & Südhof, 2009 ). Botulinum neurotoxins, a class of bacterial poisons, target various proteins of this exocytotic machinery leading to a failure in neurotransmission and eventual paralysis (Pirazzini, Rossetto, Eleopra, & Montecucco, 2017 ). Following exocytosis, endocytosis rapidly recycles vesicles, vesicular membrane proteins and sustains further exocytosis. NSF, neurexin, and α‐SNAP are known to be involved with the disassembly of SNAREs following exocytosis and play a crucial role in maintaining fusion dynamics and vesicle recovery within the synapse (C. Zhao, Slevin, & Whiteheart, 2007 ).

4.2. The synaptic space and the synaptic basal lamina

Space between the pre‐ and postsynaptic membranes through which ACh diffuses, is divided into the primary cleft (bounded by the presynaptic membrane and the basement membrane) and the secondary clefts (space between the junctional folds of the postsynaptic membrane). Center of the synaptic cleft is occupied by the synaptic BL (basement membrane, BL). In addition to a mechanical role, synaptic BL plays an important role in NMJ innervation, development and regeneration, specifying architecture and physiological roles of pre‐ and postsynaptic membranes in both normal and disease pathology (Sanes, 2003 ). Components of the synaptic BL include laminins (4, 9, and 11) (Rogers & Nishimune, 2017 ), collagens IV, and nidogen‐2 (Fox, Ho, Smyth, & Sanes, 2008 ). A portion of the diffusing ACh is hydrolyzed by AChE, promoting cessation of signal transmission (Soreq & Seidman, 2001 ). AChE is anchored to the BL via COLQ and perlecan (Anglister & McMahan, 1985 ; Kimbell, Ohno, Engel, & Rotundo, 2004 ). Expression of perlecan is crucial for localizing AChE to the synaptic BL (Arikawa‐Hirasawa, Rossi, Rotundo, & Yamada, 2002 ), while COLQ is suggested to control postsynaptic differentiation (Sigoillot, Bourgeois, Lambergeon, Strochlic, & Legay, 2010 ). Agrin, a NMJ heparin sulfate (HS) proteoglycan (PG), critical for organization of the ACh receptors and NMJ, is found in the BL along with neuregulin which acts downstream of agrin (Mc Mahan, 1990 ). ECM in the synaptic space also plays a role in, reinnervation (Glicksman & Sanes, 1983 ; Sanes, Marshall, & McMahan, 1978 ) and synaptic adhesion (Yamagata, Sanes, & Weiner, 2003 ).

4.3. Postsynaptic region

Postsynaptic region consists of junctional folds, which amplify the postsynaptic membrane area and consequently the volume of synaptic space, and the junctional sarcoplasm (Figure ​ (Figure5). 5 ). Junctional sarcoplasm fills the synaptic space and contains several cellular structures such as mitochondria, Golgi apparatus, and intermediate filaments (IFs), required to meet the metabolic and structural needs of the postsynaptic region.

The terminal expansions (crests) of the junctional folds are packed with nicotinic acetylcholine receptors (nAChRs) which are pentameric ion channels with subunits α, β, γ, δ, and ε (Kramer, 2016 ) which are linked via rapsyn (Zuber & Unwin, 2013 ). ACh that reaches the postsynaptic membrane activates nAChRs, creating a local depolarization potential. Under normal physiological conditions, nAChR are impermeable to Cl − ions but allow Na 2+ and K + ions and to a lesser extent Ca 2+ and Mg 2+ ions. The magnitude and direction of current through the nAChRs depends however on the membrane potential. This in turn activates the voltage‐gated sodium channels (VGSCs) concentrated in the troughs of junctional folds (Awad et al., 2001 ), along with neural cell adhesion molecule (Rafuse, Polo‐Parada, & Landmesser, 2000 ), creating an action potential which is transmitted through the fiber via the T‐tubules. Ankyrin‐G and β‐spectrin are essential for maintaining VGSC densities in the postsynaptic folds, necessary for impulse propagation (Flucher & Daniels, 1989 ; Tee & Peppelenbosch, 2010 ; Wood & Slater, 1998 ). MUSK a master regulator of NMJ development is suggested to induce AChR clustering via agrin and its co‐receptor, LRP4 (Zong et al., 2012 ). Detailed reviews of agrin associated signaling via muscle‐specific and cytoskeletal proteins (e.g., MUSK, LRP4), necessary for AChR clustering and formation of postsynaptic structures are presented in Bezakova and Ruegg ( 2003 ) and H. Wu, Xiong, and Mei ( 2010 ) (Figure ​ (Figure6 6 ).

The sequence of cellular events associated with synaptic signaling that activates the cascade of downstream events towards muscle contraction are identified here

Additionally, research has indicated important organizational roles for amyloid precursor proteins (APP, APLP1, APLP2) specifically trans‐adhesion of the post‐ and presynaptic membranes via their interaction with LRP4 and agrin at the NMJ (H. Y. Choi et al., 2013 ; Klevanski et al., 2014 ). Neuregulin (a neural trophic factor similar to agrin) and its receptors ERBB2/3/4 aggregate on the postsynaptic membrane. Neuregulin/ERBB signaling is suggested to function in stabilizing agrin‐induced AChR clusters, via phosphorylation of αDystrobrevin‐1, subsequently maintaining organization of the adult NMJ (Schmidt et al., 2011 ).

Myasthenia gravis (MG, acquired, neonatal and congenital) represent the largest group of progressive disorders caused due to impaired signal transmission across the motor end plates due to perturbations to a single (SCN4A mutations, Tsujino et al., 2003 ) or multiple proteins associated with postsynaptic membrane (nAChR degradation or its associated proteins; rapsyn, agrin, etc.; Engel, 2014 ). MG is characterized first by loss of control and weakness in eye muscles, followed by throat and neck and subsequently limb muscles. Majority of the acquired and neonatal MG cases are associated with IgG antibody cross‐linking of the postsynaptic nAChRs, resulting in the reduction of the number of effective receptors. Autoantibody binding, results in increasing degradation or nAChRs and subsequent damage to the postsynaptic membrane and its dynamics with synaptic folds, leading to impacted muscle contraction (Hirsch, 2007 ). Recent research has also shown mutations in COL13A1 (a transmembrane collagen shown to regulate synaptic integrity via its binding to COLQ) resulting in a novel subtype of congenital MG (Härönen et al., 2017 ; Logan, Cossins, Cruz, et al., 2015 ).

5. EXCITATION CONTRACTION COUPLING

Muscle contraction begins with the activation of fast sodium channels (postsynaptic voltage channels, SCN4A), generating an action potential that is transmitted to the muscle fiber, initiating contraction. This process, called ECC occurs at the junction between two membranous structures, namely, the transverse tubules (T‐tubules) and the sarcoplasmic reticulae, called the triad junction (Figure ​ (Figure1 1 for a birds‐eye view, Figure ​ Figure7). 7 ). The transmitted nerve action potential depolarizes the dihydropyridine receptor (DHPR) of the T‐tubules, a voltage‐gated Ca 2+ channel (VGCC L‐Type), which in turn triggers the intracellular release of a large bolus of Ca 2+ from the sarcoplasmic reticulum (SR) terminal cisternae via the ryanodine receptors (RYRs, calcium release channels). DHPR is suggested to act as a voltage sensor in skeletal muscle, and controls the opening of RYRs through direct molecular interactions (Franzini‐Armstrong, 2004 ). Dominant point mutations in DHPR (Ptáček, Tawil, Griggs, et al., 1994 ), and in SCN4A (Jurkat‐Rott et al., 2000 ), are associated with hypokalemic periodic paralysis, a disease characterized by muscle weakness/loss in fiber strength at low extracellular potassium levels.

A schematic representation of the important molecular actors involved in excitation contraction coupling at the triad junction. DHPR, RYR1, SERCA pump, along with calsequestrin form the main proteins responsible for Ca 2+ cycling and storage within the sarcoplasmic reticulum. Calsequestrin is a high capacity Ca 2+ binding protein found in dense, highly concentrated filamentous matrices within the terminal cisternae of sarcoplasmic reticulum. JPH1 and MG29, are suggested to play significant roles in maintaining the structural integrity of this junction

In healthy cells, large amounts of Ca 2+ are effectively sequestered in the vicinity of RYRs, within the SR lumen by calsequestrin (CASQ). CASQ, a very high affinity Ca 2+ binding protein, sequesters large amounts of Ca 2+ in densely concentrated filamentous matrices within the terminal cisternae of SR (Beard, Laver, & Dulhunty, 2004 ) and is suggested to regulate RYR dynamics (Beard et al., 2005 ) affecting muscle contractility. Two proteins, mitsugumin29 (MG29) and junctophilin function to maintain the structural and functional integrity of the triad junction. Junctophilin physically docks SR to the T‐tubule (Takeshima, Komazaki, Nishi, Iino, & Kangawa, 2000 ) maintaining the spatial proximity and MG29 is suggested to co‐localize within the junction (N. R. Brandt & Caswell, 1999 ; Takeshima, Shimuta, Komazaki, et al., 1998 ) and is necessary for efficient signal transduction of ECC between the SR and T‐tubules (Komazaki, Ito, Takeshima, & Nakamura, 2002 ; Nishi et al., 1999 ). Two other integral membrane proteins triadin (which aids in sequestering of CASQ) and junctin (a CASQ binding protein) are both suggested to form a quaternary complex with CASQ and RYR and are required for the normal regulation of Ca 2+ release (Györke, Hester, Jones, & Györke, 2004 ; L. Zhang, Kelley, Schmeisser, Kobayashi, & Jones, 1997 ). RYR1 interacts with several other proteins integral to the SR such as FKBP1A, Homer, and calmodulin (CaM) leading to tight regulation of Ca 2+ concentrations for efficient coupling and force generation. FKBP1A and Homer are essential for stabilization, and proper functioning of the Ca 2+ release channels within muscle (Avila, Lee, Perez, Allen, & Dirksen, 2003 ; Pouliquin & Dulhunty, 2009 ). CaM, a soluble Ca 2+ binding protein binds RYR and activates/inhibits its function depending on cytosolic Ca 2+ concentration (Tripathy, Xu, Mann, & Meissner, 1995 ). Ca 2+ /CaM‐dependent protein kinases (CaMK), specifically CaMKII, associated with the terminal cisternae of SR are shown to phosphorylate a series of proteins within the SR and regulate their function directly affecting ECC (Chin, 2005 ). A newly discovered Z‐disk protein NRIP, is suggested to activate CaMKII throughCa 2+ ‐dependent binding with CaM regulating mitochondrial function, slow myosin expression and muscle regeneration (Chen et al., 2015 ). Recent studies have identified S100A1 as a physiological modulator of RYR1, which structurally alters the RYR1/CaM complex suggesting complex dynamics between the three players at varying Ca 2+ concentrations (Rebbeck et al., 2016 ).

Genetic defects in Ca 2+ release channels (RYR1) are associated with two diseases classified broadly under congenital myopathies, namely, malignant hyperthermia (MH) and central core disease (CCD). CCD is a rare, inherited, non‐progressive myopathy characterized by loss in muscle tone and muscle weakness, accompanied often by MH (Jungbluth, 2007 ). Patients with MH exhibit adverse responses to inhalational anesthetics and muscle relaxants. Physiologically, in the presence of triggering agents such as anesthetics, mutated release channels (i.e., RYR1) flood the cell with spontaneous and enhanced rates of Ca 2+ , overpowering the Ca 2+ pump action. Sustained muscle contractions lead to muscle rigidity, with increased rates of glycolytic metabolism, lactic acid production, CO 2 and heat combined with an enhanced oxygen uptake. Loss of ion homeostasis and associated membrane damage lead to other life‐threatening systemic problems (hypoxemia, hyperkalemia, ventricular fibrillation, renal failure, and cyanosis) and in many cases, death (Loke & MacLennan, 1998 ).

The elevation of cytosolic Ca 2+ brings a conformational change in troponin, beginning the cascade to muscle contraction. In contrast, muscle relaxation is brought about by removal of cytosolic Ca 2+ and is associated with high chemical energy requirements. ATP‐dependent Ca 2+ ATPase (SERCA pumps) densely packed on the non‐junctional face of the SR terminal cisternae function to return cytosolic Ca 2+ released into the terminal cisternae (Periasamy & Kalyanasundaram, 2007 ). Three homologous ATP2A genes have been identified to encode three SERCA isoforms and their splice variants, with SERCA1a being ubiquitously expressed in mature skeletal muscle and SERCA1b in immature (fetal and neonatal) skeletal muscle. Additionally, SERCA1a binds sarcolipin (SLN) and phospholamban (PLN) (two homologs) that at low Ca 2+ cytosolic concentrations significantly reduce SERCA's affinity to Ca 2+ , bringing about muscle relaxation (Espinoza‐Fonseca, Autry, & Thomas, 2015 ). Sarcalumenin (SRL), a luminal glycoprotein, plays a role in maintaining protein stability of SERCA pumps as well as buffering of Ca 2+ in skeletal and cardiac muscles (Yoshida et al., 2005 ). Parvalbumin, a high Ca 2+ affinity protein, present in the soluble sarcoplasm acts as a relaxing factor by binding free Ca 2+ and is directly correlated with relaxation speeds of mammalian fast muscle (Rall, 1996 ).

Excitation contraction coupling results in the contraction of the sarcomeric machinery as outlined in the next section.

6. MUSCLE CONTRACTION AND FORCE GENERATION

6.1. the sarcomere.

Force generation and rapid movement are hallmarks of striated muscle function brought about by contraction of the sarcomere. Sarcomeres represent an elegant piece of molecular machinery whose complex structure is composed of two main alternating sets of protein filaments: thin filaments (α‐actin and associated proteins) and thick filaments (myosin and associated proteins) which run parallel to the muscle fiber axis. Visually, the sarcomere is bordered at each end by a dark narrow line called the Z‐disk. Each Z‐disk bisects a lighter I band which is shared between adjacent sarcomeres. At the center of the sarcomere is a dense A‐band made up of thick filaments, with a lighter H‐zone. The M‐line bisects the H‐zone. Thin filaments are held together, in a lateral array, at the Z‐disk while the M‐band interconnects the thick filaments (Figure ​ (Figure8a; 8 a; Huxley, 1957 ). Functionally, contraction begins with the binding of troponin‐C with the Ca 2+ released during ECC. This brings about a conformational change in the troponin‐tropomyosin complex resulting in the exposure of myosin binding sites on the actin filaments Myosin heads then bind and crawl along the length of the actin filament bringing about hydrolysis of ATP and subsequently contraction (Huxley, 1969 ; Huxley & Kress, 1985 ).

(a) Schematic representation of the striated skeletal muscle sarcomere showing the arrangement of thick and thin filaments in the sarcomere and identifying bands of overlap between them. (b) Schematic diagram of the sarcomere summarizing organization and location of major sarcomeric proteins. Cytosolic Ca 2+ brings about a conformational change in the structure of troponin C, revealing myosin binding sites. Myosin heads successively bind and crawl along the length of actin, bringing about sarcomeric contraction. Titin and nebulin, function as “molecular templates” maintaining the length of the thick and thin filaments, respectively. A whole host of proteins within the M‐line and Z‐disk function mainly to maintain structural integrity of thick and thin filament lattices, respectively. The desmin intermediate filaments reinforce and integrate the structure of the muscle cell by forming transverse links between adjacent myofibrils

The following sections briefly outline the major sarcomeric proteins, the mechanism of sarcomeric contraction, fiber types and their roles in health and disease (Clark, McElhinny, Beckerle, & Gregorio, 2002 ; Figure ​ Figure8 8 b).

6.1.1. Thick filament

The thick filament is mainly composed of myosin proteins. Myosin is both an enzyme as it hydrolyzes ATP (head) and a structural protein (tail) and is associated with other non‐myosin proteins with specialized (mostly structural) functions such as myosin binding proteins (MyBPs) C and H of the M‐band. MyBPCs are an important class of MyBPs that contribute to myosin's precise organization and regulate force generation by the actomyosin complex (Ackermann & Kontrogianni‐Konstantopoulos, 2013 ). MyBPC is found associated with titin (Freiburg & Gautel, 1996 ) and as transverse stripes within the sarcomeric A‐band (R. Gilbert, Cohen, Pardo, Basu, & Fischman, 1999 ). The giant elastic protein, titin, extends along the length of the thick filament, as far as the Z‐line ensuring that equal forces are developed in the two halves of the A‐band in a mature muscle (K. Wang, McClure, & Tu, 1979 ). For a more detailed review of the titin gene and protein function, the reader is suggested a recent review by Linke ( 2018 ). Developmentally titin is suggested to act as a “molecular template,” a ruler, for defining the precise length and organization for myosin filaments (Horowits, Kempner, Bisher, & Podolsky, 1986 ).

As observed in Oldfors ( 2007 ), a new group of muscle diseases called “hereditary myosin myopathies” have emerged, associated mainly with myosin mutations. They broadly represent at least five different muscle diseases including myosin storage myopathy (MSM). MSM is a slowly progressing, relatively mild congenital myopathy characterized by accumulation of myosin in Type I muscle fibers. Other diseases included the Freeman–Sheldon and Sheldon–Hall syndromes as a result of MYH3 mutations, dominant inclusion body myopathy caused by mutations in fast myosin IIA and distal arthrogryposis trismus pseudocamptodactyly syndrome caused by mutations in perinatal MYH (reviewed in Laing & Nowak, 2005 ; Oldfors, 2007 ).

A whole class of proteins at the M‐band/M‐line, associate myosin with titin, which function to stabilize the transverse and longitudinal order of the thick filament lattice and link neighboring filaments for coordinated contraction of the sarcomeres (Hu, Ackermann, & Kontrogianni‐Konstantopoulos, 2015 ). Myomesin is one of the main proteins of the M‐line that are suggested to function as strain sensors within the sarcomere (Xiao & Gräter, 2014 ). Anti‐parallel dimers of myomesin link myosin filaments at the M‐line, and are linked in a ternary complex with obscurin and titin (Gautel & Djinović‐Carugo, 2016 ; Pernigo et al., 2015 ; Pernigo, Fukuzawa, Beedle, et al., 2017 ). Obscurin, serves as ligand for small ankyrin‐1, a protein integral to the network SR (Ackermann et al., 2011 ; Kontrogianni‐Konstantopoulos, Catino, Strong, et al., 2006 ; Kontrogianni‐Konstantopoulos, Jones, Van Rossum, & Bloch, 2003 ) and is suggested to regulate alignment of the network SR around the sarcomere (Kontrogianni‐Konstantopoulos et al., 2006 ). Creatine kinase, present in the M‐band binds to myosin and acts as spatial ATP buffer, essential for maintaining energy homeostasis and serving immediate ATP requirements of the sarcomere (Wallimann & Eppenberger, 1985 ; Wallimann, Schlösser, & Eppenberger, 1984 ). The presence of this protein kinase at the M‐band suggests an additional enzymatic role for the M‐band within the sarcomere. The M‐line also serves as a scaffold for a number of components of the protein turnover machinery via ubiquitin‐mediated turnover (Durham et al., 2006 ; Sarparanta et al., 2010 ) and is suggested to be involved in cytoskeletal remodeling (Hu et al., 2015 ).

6.1.2. Thin filament

Actin isoforms polymerize to form thin filaments, an essential part of the contraction machinery. Similar to thick filaments, thin filaments are associated with a host of proteins that facilitate contraction. The most important are troponin (TNN‐I, the inhibitory subunit that binds to actin; TNN‐C, the calcium binding subunit and TNN‐T, the tropomyosin binding component) and tropomyosin that functions to stabilize actin and provide a molecular scaffold for positioning the Ca 2+ ‐sensitive troponin molecule on the filament (reviewed in Zot & Potter, 1987 ). Ca 2+ released upon fiber depolarization, raises the free Ca 2+ concentration in cytosol, binding to Ca 2+ ‐specific sites of TNN‐C, forming the initial signal for myofribrillar contraction, with changes propagating to TNN‐I/TNN‐T structure. These changes influence the troponin/tropomyosin and subsequently its interaction with actin, revealing sites for myosin binding on the actin filament (Galińska‐Rakoczy et al., 2008 ). Similar to titin, nebulin functions as a molecular template for thin filaments (Horowits et al., 1986 ). Tropomodulin, the capping protein for the pointed end of actin, prevents polymerization or depolymerization of actin thus maintaining the precise filament length necessary for efficient contraction (Gokhin, Ochala, Domenighetti, & Fowler, 2015 ).

Mutations in genes encoding skeletal muscle actin, tropomyosin, TNN‐T and nebulin result in molecular defects causative of a group of muscle disorders largely defined as congenital myopathies (particularly, nemaline rod myopathy). A detailed review, its clinical relevance and management is provided in Jungbluth et al. ( 2018 ) and Nance, Dowling, Gibbs, and Bönnemann ( 2012 ).

6.1.3. Z‐disk

The Z‐disk/Z‐line anchors and cross‐links anti‐parallel actin filaments in a regular lateral array and connects repeating sarcomeres into the linear array of the myofibril. A large proportion of known sarcomeric proteins are identified within the Z‐disk including α‐actinin, myozenins, myotilin, myopalladin, myopodin, γ‐filamin, γ‐actin (Papponen, Kaisto, Leinonen, Kaakinen, & Metsikkö, 2009 ), muscle LIM protein (MLP), desmin, overlapping portions of thin filaments (nebulin, actin), titin and the more recently discovered NRIP protein (Chen et al., 2015 ; see Section 5 ).

α‐Actinin is a key structural component and cross‐linking protein of the Z‐disk. It also connects titin molecules from opposing sarcomere halves (Luther, 2009 ). Capping proteins for actin, CapZ (Yamashita, Maeda, & Maéda, 2003 ) and for titin‐telethonin/TCAP (Valle, Faulkner, De Antoni, et al., 1997 ; Zou et al., 2006 ), are located within the Z‐disk. Myopalladin (Bang et al., 2001 ) links nebulin to α‐actinin subsequently anchoring nebulin to the Z‐disk. It also interacts with titin and ANKRD1, suggesting a role in the stretch sensor system within the muscle. Myopodin, an actin bundling protein, co‐localizes with α‐actinin, γ‐filamin (Linnemann et al., 2010 ), synaptopodin 2‐like (Beqqali et al., 2010 ) and is suggested to participate in signaling between the nucleus and the Z‐disk during development and cellular stress. Myozenin binds to several Z‐disk proteins α‐actinin, γ‐filamin (Takada et al., 2001 ) and myotilin (Gontier et al., 2005 ) and is suggested to influence the dimerization and subsequent lateral spacing of thin filaments at the Z‐disk. Studies in exercise‐induced muscle remodeling have identified a translocation of myotilin from the Z‐disk to M‐bands (Carlsson, Yu, Moza, Carpén, & Thornell, 2007 ). MLPs are suggested to play role in mechano‐sensing (via costameric proteins; Flick & Konieczny, 2000 ) and actin dynamics (bundling and cross‐linking; Hoffmann et al., 2014 ).

Mutations in Z‐disk genes (myotilin, T‐cap, and titin) are associated with a form of dystrophy called limb‐girdle muscular dystrophy (LGMD; W.‐C. Liang & Nishino, 2015 ). LGMD are a genetically heterogeneous disease group, clinically characterized by progressive weakness of first proximal and then distal muscles. Myotilin, along with two other Z‐disk associated proteins, desmin and αB‐crystallin have also been implicated in myofibrillar myopathies characterized by abnormal myofibrillar degradation and accumulation of degradation products (Selcen & Engel, 2004 ).

In addition to the diseases specifically mentioned in the sections above, mutations in several sarcomeric proteins are also the cause for a major class of inherited diseases that affect cardiac mass and function called familial hypertrophic cardiomyopathy (FHC). Over 100 mutations have been identified in cardiac isoforms of thick, and thin filament proteins such as MYH7, TNNT2, TNNI3, TPM1, MYOZ2, MYL2, ACTC1, TCAP, MYBPC3, and TTN as contributing to FHC (reviewed in Bonne, Carrier, Richard, Hainque, & Schwartz, 1998 ; Marian, 2008 ).

6.2. Force generation

It is understood that muscle fibers have a consistent fiber diameter between muscles of different sizes and fiber size is directly proportional to fiber force generation. However, architecturally, how the myofibers arrange themselves with respect to the force‐generating axis demonstrates the versatility of muscle function. Three main classes of muscle architecture have been identified (Lieber & Friden, 2000 ): (a) longitudinal, where myofibers run along the length of muscle's force‐generating axis (e.g., biceps); (b) unipennate in which myofibers run along a fixed angle of the axis (e.g., vastus lateralis muscle); and (c) multipennate architecture in which muscle fibers run at several angles relative to the muscle's force‐generating axis (e.g., gluteus medius muscle).

At a molecular level, the sarcomeric contraction is a movement of the myosin heads on actin filaments—called cross‐bridge cycle. The cross‐bridge cycle is a sequence of enzymatic reactions responsible for movement of myosin heads on actin filaments, generating force within each individual myofibril, which is collectively experienced by the muscle. Briefly, force generation occurs in six steps and is summarized as follows (Fitts, 2008 ; Figure ​ Figure9). 9 ). At the onset of contraction, free cytosolic Ca 2+ brings a conformational change in troponin, revealing myosin‐binding sites on actin filaments. Myosin head swings out towards the thin filament at a 45° angle and is in a rigor (stiff) state. Available ATP binds to myosin, briefly dissociating myosin from actin. The ATPase activity of myosin hydrolyzes ATP to ADP and Pi (free phosphate) (still bound to myosin) causing the myosin filament to weakly rebind actin at the 90° angle (cross‐bridge) relative to the actin filament. The release of Pi initiates the power stroke. The myosin head rotates on its hinge pushing the actin filament past it, towards the M‐band. At the end of the power stroke, myosin head releases ADP and regains its rigor state.

Cellular events underlying force generation. Force generation begins with arrival of an impulse, which changes the Ca 2+ dynamics within muscle leading to a highly orchestrated set of specific changes to the molecular structure of the actomyosin complex bringing about sarcomeric contraction

6.3. Fiber types

Force generation depends on the size and fiber type composition of skeletal muscle. Four types of muscle fibers (within two major fiber types) dominate skeletal muscle, namely slow‐twitch (Type I) and fast‐twitch (Type II) fibers containing subtypes IIA, IIB, and IIX. It is recognized that the pattern of Type II fiber specialization depends on expression patterns of myosin heavy chains isoforms during histogenesis (Rubinstein & Kelly, 2004 ).

Phenotypically, slow‐twitch or Type I muscle is highly vascularized and saturated with mitochondria and myoglobin exhibiting high mitochondrial and oxidative enzyme content with low glycolytic activity. Slow‐twitch fibers are resistant to fatigue, relying on oxidative metabolism for energy, while contracting for long periods with little force generated. Type I fibers are found more abundantly in elite endurance athletes (e.g., swimmers). Fast‐twitch or Type II muscle, exhibit faster contraction times, sustaining short anaerobic bursts of activity, fatiguing easier than Type I fibers. Type II fibers have a high glycolytic capacity ensuring adequate ATP generation to compensate for the accelerated rate of ATP hydrolysis. For this reason, a higher proportion of Type II fibers can be seen in elite strength and power athletes (e.g., sprinters, weight lifters). Of the three major subtypes (IIA, IIX, and IIB), that vary in both contractile speed and force generation. IIA fibers are similar to slow‐twitch in the sense that they have more myoglobin and depend more on oxidative metabolism.

Physiologically, the difference between fast‐ and slow‐twitch muscles is based on differences in their calcium kinetics, ECC mechanisms, and molecular motor activity, which governs the basic twitch parameters (time to peak tension and half‐relaxation time). Fast fibers exhibit shorter twitch parameters, and rapid contraction of the sarcomere. Fast fibers allow for generation of fast and large calcium transients, contributed by lower cystolic‐free Ca 2+ , reduced Ca 2+ entry from extracellular space, and greater abundance of RYRs and SERCA pumps (Reggiani & Te Kronnie, 2006 ). Fast fibers are endowed with a powerful contractile machinery primarily due to differing myosin isoforms (MYH2 in IIA, MYH4 in IIB, and MYH1 in IIX fibers, respectively) exhibiting rapid sarcomeric shortening velocity and higher mechanical power. Slow fibers contract much more slowly, generating less mechanical power with lesser ATP expenditure, making them (fiber subtypes) metabolically diverse (Rivero, Talmadge, & Edgerton, 1998 ).

Genetically, each muscle fiber type is equally diverse with different thick and thin filament isoforms being expressed in slow and fast muscle. For instance, MYH7, MYL2/3, MYBL2, TNNT1/I1/C1, TPM3, TMOD1, ATP2A2, and CASQ2 represent slow fiber isoforms, while MYL1, MYBP2, TNNT3/I1/C2, TPM1, TMOD4, ATP2A1, CASQ1 all represent fast fiber isoforms.

6.3.1. Fiber‐type remodeling and the effect of exercise on fiber types

Skeletal muscle fibers exhibit remarkable plasticity, an ability to undergo adaptive changes, in response to physical activity (exercise) or inactivity (disuse, disease, injury). Studies have identified mechanisms necessary for specifying fiber type during development and maintaining or switching fiber types thereafter. For instance, Buller, Mommaerts, and Seraydarian ( 1969 ) first demonstrated fiber type switching in cats as a result of changes in nerve activity. The role of exercise in fiber‐type remodeling and muscle function is well studied in the context of sports physiology (Wilson et al., 2012 ), and, is of importance in metabolic diseases and cardiovascular health. For instance, exercise in human and animal models is shown to induce a switch in fiber types to a more oxidative fast fiber phenotype (IIX → IIA in humans, and IIB → IIX → IIA in rats and mice with a nonsignificant switch to a slow phenotype (Ausoni, Gorza, Schiaffino, Gundersen, & Lomo, 1990 ). Fiber‐type switching has been evidenced to involve signaling mechanisms containing the calcineurin‐NFAT signaling pathway as reported in a seminal paper by Chin et al. ( 1998 ); bidirectional promoters (which can generate both sense and antisense transcripts located in the vicinity of MYH genes; Rinaldi et al., 2008 ), and/or miRNAs (located within the MYH genes; van Rooij et al., 2009 ). MYH gene expression and fiber type profile (as a result of disease or exercise) are also known to be affected by the activity of genes such as MEF2 (H. Wu et al., 2000 ), PPAR‐β/δ (Schuler et al., 2006 ; Y.‐X. Wang et al., 2004 ), activated protein kinase (AMPK; Lee‐Young, Canny, Myers, & McConell, 2009 ), and PGC1‐α (Handschin et al., 2007 ; Lin et al., 2002 ).

Studies in various animal and human models of disease and injury have additionally shown that both skeletal and cardiac muscle fibers begin to express embryonic and developmental isoforms, such as MYH3 and MYH8 (Mukund & Subramaniam, 2015 ; Mukund, Ward, Lieber, & Subramaniam, 2017 ; Taegtmeyer, Sen, & Vela, 2010 ), possibly contributing to observed changes in muscle force and resistance to fatigue. A detailed and versatile review on the functional, physiological and mechanistic differences between muscle fiber types is provided in Schiaffino and Reggiani ( 2011 ).

7. EXTRACELLULAR MATRIX

Connective tissue of muscle is a complex entity, comprising of non‐contractile ECM with embedded fibroblasts and macrophages and an extensive network of capillaries and nerves, flexible enough to adjust to contraction–relaxation cycles. ECM is multifunctional within muscle and enables uniform distribution and transmission of force within muscle and from muscle to tendon (along BL). ECM also serves as a scaffold for cell matrix interactions (focal adhesion) necessary for a host of biological responses within the muscle (Grzelkowska‐Kowalczyk, 2016 ). The cytoskeleton‐ECM‐reticular linkage (via the dystrophin associated protein complex, DAPC) has been shown to be crucial for providing necessary biomechanical support and handling contraction (stretch) stresses within the muscle, behaving as a key modulator for maintaining mechanical homeostasis within the muscle (Humphrey, Dufresne, & Schwartz, 2014 ).

Traditionally, ECM in skeletal muscle is organized into three discrete but interconnected structures: epimysium, perimysium, and the endomysium. The epimysium, a dense connective tissue layer encapsulates the entire muscle while the perimysium derives from the epimysium and surrounds the fascicles (bundles of muscle fibers). The endomysium or basement membrane (comprising of an inner BL [adjacent to the sarcolemma] and an outer reticular lamina) is a delicate layer of ECM surrounding each myofiber. This gross classification is in much debate given our increasing recognition of the ECM complexity in structure and function (Gillies & Lieber, 2011 ).

The ECM constitutes three main classes of proteins namely collagens, non‐collagenous glycoproteins and PGs (Figure ​ (Figure10). 10 ). Collagens represent the largest fraction of matrix proteins within the muscle (Gelse, Pöschl, & Aigner, 2003 ; Gordon & Hahn, 2010 ). Collagens I, III, V, and XI are fibrillar collagens that are capable of forming fibrils in the muscle ECM. Collagen I, a major collagen within muscle, exhibits considerable biomechanical properties including tensile strength and load bearing. Collagen VI, a microfibrillar protein forms a network of fine filaments, while collagen IV forms the most important structural component of the basement membrane integrating laminins, nidogens (Fox et al., 2008 ; Ho, Böse, Mokkapati, Nischt, & Smyth, 2008 ), and other proteins into a stable structure. Lysyl hydroxylase‐3 plays a particularly important role in the biosynthesis of functional collagen types IV and VI (Salo et al., 2008 ). Fibronectin functions as a “master organizer,” aiding in fibril organization along with fibrillin‐1 and as a bridge between proteins including integrins (α7/β1), collagen IV, PGs and other focal adhesion molecules (Halper & Kjaer, 2014 ). It also plays an essential role in the assembly of fibrillin‐1 into structured microfibrils (Sabatier et al., 2009 ). Elastin is the main component of elastic fibers (encased in layers of microfibrils and PGs) contributing to muscle elasticity (A. Gilbert, Wyczalkowska‐Tomasik, Zendzian‐Piotrowska, & Czarkowska‐Paczek, 2016 ; Kozel, Ciliberto, & Mecham, 2004 ).

A schematic representation of the main extracellular matrix proteins and their approximate localization surrounding skeletal muscle

A variety of regulatory ECM proteins are involved in matrix assembly and the modulation of cell–matrix interactions, including nidogens, periostin, and SPP1. MMPs and their inhibitors (TIMP1, TIMP2) are an important class of ECM‐associated enzymes that maintain ECM integrity and regulate ECM protein degradation (Arpino, Brock, & Gill, 2015 ; S. Murphy & Ohlendieck, 2016 ). A variety of PGs (such as hyaluronan), chondroitin sulfate/dermatan sulfate PGs (such as versican; Nandadasa, Foulcer, & Apte, 2014 ), small leucine‐rich repeat PGs (e.g., biglycan, decorin, lumican, fibromodulin) and HS PGs (e.g., syndecan, perlecan, agrin) have been identified to be distributed between the collagen fibers (Halper & Kjaer, 2014 ). HA is a large, linear glycosaminoglycan highly expressed in muscle during development (Tammi et al., 2011 ). Biglycan interacts with α‐sarcoglycan and γ‐sarcoglycan (Bowe, Mendis, & Fallon, 2000 ), while decorin, a known inhibitor of TGF‐β, is the primary PG molecule of the perimysium (J. Zhu et al., 2007 ). Syndecan, perlecan, and agrin are found associated with the basement membrane and co‐operate with integrins to facilitate cell–ECM interactions (Sarrazin, Lamanna, & Esko, 2011 ). Several of the above‐mentioned proteins serve as important signaling mediators that directly influence muscle regeneration, wound healing and recovery (Aya & Stern, 2014 ; Y. Li et al., 2007 ; Schultz & Wysocki, 2009 ). Production and maintenance of these ECM components is tightly regulated by a host of growth factors sequestered at the ECM including connective tissue growth factor (regulates collagen gene expression), HGFs (regulate quiescent satellite activation), FGFs (stimulate angiogenesis and regulate fibroblast proliferation and action), and TGFβ (regulate fibroblast and ECM expression) (Flaumenhaft & Rifkin, 1991 ). ECM at the NMJ plays a crucial role in the organization and interaction between the nerve terminal and muscle fiber as outlined in Section 4.2 .

7.1. ECM in pathology

Muscle is capable of regenerating and should ideally recover completely upon injury. However, muscle ECM composition and function are dramatically affected after chronic/acute injury arising from disease (Carmignac & Durbeej, 2012 ), diet (Tam, Power, Markovic, et al., 2015 ), poisons/pathogens (Mukund et al., 2017 ), Crum‐Cianflone (Crum‐Cianflone, 2008 ), and age (Stearns‐Reider et al., 2017 ). Insulin resistance, the hallmark of diabetes, is tightly linked with ECM remodeling and deposition of ECM proteins such as collagens, laminins and fibronectin, predisposing diabetes (Ban & Twigg, 2008 ; Fukui et al., 1992 ; A. S. Williams, Kang, & Wasserman, 2015 ). Studies stimulating chronic/acute muscle and nerve injury have repeatedly identified ECM expansion as a crucial step in muscle recovery, particularly at the BL. Mutations of laminin α2 and collagen VI of the synaptic BL have more recently been identified to be causative of congenital muscular dystrophy (Muntoni & Voit, 2004 ). In models of chronic/acute injury, rapid fiber necrosis is observed immediately upon injury, resulting in the activation of the complement cascade and infiltration of leukocytes and neutrophils followed by monocytes (macrophages). Phagocytic macrophages clear damaged myofibers and produce anti/pro‐inflammatory cytokines such as TGFβ and TNFα, which regulate cell migration, proliferation and muscle regeneration (Philippou, Maridaki, Theos, & Koutsilieris, 2012 ). In muscle recovery, resident fibroblasts are transformed into myofibroblasts (which synthesize ECM components such as fibrous collagens I and III and BL collagens IV and VI; Chapman, Mukund, Subramaniam, Brenner, & Lieber, 2017 ), bringing about an expansion of ECM proteins. Several myopathies and dystrophies are associated with mutations in several ECM genes such as decorin, perlecan, syndecan (Van et al., 2017 ) as outlined in Supplementary Table 2 .

7.1.1. Fibrosis

In most pathologies, the initial ECM expansion process becomes uncontrolled, leading to a substantial remodeling of muscle ECM. This uncontrolled and irreversible ECM expansion accompanied by an accumulation of ECM due to inhibited degradation (turnover), results in a fibrotic phenotype within muscle (Mann et al., 2011 ), especially in chronic diseases such as dystrophinopathies (Serrano & Muñoz‐Cánoves, 2017 ). The chronic and sustained inflammatory response in dystrophic muscle serves as a positive feedback mechanism prolonging macrophage activity, release of inflammatory cytokines and increased ECM production (Serrano & Muñoz‐Cánoves, 2010 ). We have previously also shown evidence for fibrosis in muscle injected with botulinum neurotoxin A (Mukund et al., 2014 ).

TGFB1, a secreted cytokine of M2 (anti‐inflammatory) macrophages is a crucial regulator of fibroblast activity and collagen synthesis and accumulation in wound healing and repair (Biernacka, Dobaczewski, & Frangogiannis, 2011 ). Though the precise molecular mechanism of TGFβ action on fibroblasts is yet to be understood, it is suggested to stimulate transition of resident fibroblasts into myofibroblasts (key effector cells for ECM production, and in pathology fibrosis), via the SMAD pathway (Evans, Tian, Steadman, & Phillips, 2003 ) and in a SMAD independent manner involving PI3K/AKT pathway (Conte et al., 2011 ; Wilkes, Mitchell, Penheiter, et al., 2005 ). Myostatin has been shown to directly influence fibrosis and fibroblast activation via the p38MAPK and AKT pathways (Z. B. Li, Kollias, & Wagner, 2008 ). The myofibroblast phenotype is characterized by formation of gap junctions and the expression of α‐smooth muscle actin (incorporated into the newly formed contractile bundles imparting contractility and facilitating repair), fibronectin and non‐muscle myosin (MYH10) (Baum & Duffy, 2011 ). Recent studies in cardiac and skeletal muscle have identified scleraxis (SCA), a transcription factor, as being critical for regulating expression of resident fibroblasts and myofibroblasts (Bagchi et al., 2016 ; Mendias et al., 2012 ).

Additionally, mesenchymal transition of fibro/adipogenic progenitor (FAP) in regenerating/degenerating fiber microenvironments has been implicated in contributing to an activated fibroblast population (Joe, Yi, Natarajan, et al., 2010 ; Uezumi, Fukada, Yamamoto, Takeda, & Tsuchida, 2010 ; Uezumi, Ikemoto‐Uezumi, & Tsuchida, 2014 ). In addition to the well accepted role of macrophages in muscle regeneration (Tidball & Villalta, 2010 ), a more recent study highlighted their role in “directing” muscle fate between regeneration and fibrosis, by maintaining a balance between apoptotic TNFα (from M1 macrophages) and anti‐inflammatory TGFβ (TGFB1, from M2 macrophages) (Lemos, Babaeijandaghi, Low, et al., 2015 ). This balance appears to be essential for maintaining FAP population homeostasis in regenerating/degenerating fiber microenvironment (Muñoz‐Cánoves & Serrano, 2015 ). Briefly, the sequence of expression with an early wave of TNFα expression followed by a later wave of TGFβ is crucial for healthy muscle regeneration. A loss of this sequential progression under acute/chronic inflammatory conditions causes elevated TGFβ which stimulates differentiation of FAPs into fibroblasts contributing to fibrotic phenotype.

8. CYTOSKELETON

The plasticity of muscle, that is, the ability to not self‐destruct after repeated stresses of contraction and relaxation, can be attributed to the complex, and yet‐to‐be fully understood muscle cytoskeleton. The muscle cytoskeleton serves as the structural and supportive scaffold for sarcomeres within the muscle. The cytoskeletal framework consists of the following major components (Figure ​ (Figure11): 11 ): (a) a sub‐sarcolemmal network that mediates attachment of several cytoskeletal proteins to the sarcolemma; (b) a transverse connecting system anchored to the sub‐sarcolemmal network; (c) the protein complex that connects the ends of the myofibrils to the sarcolemmal folds at the myotendinous junction and longitudinally arranged microtubules running parallel and in between the myofibrils.

A schematic representation of the main cytoskeletal proteins associated with skeletal muscle. The dystrophin‐associated protein complex (DAPC) is a group of sarcoplasmic (α‐dystrobrevin, syntrophins, and nNOS), transmembrane (β‐dystroglycan, sarcoglycans, caveolin‐3, and sarcospan) and extracellular proteins (α‐dystroglycan and laminin), linking dystrophin to the extracellular matrix (ECM). Dystrophin also links to desmin, an important sarcolemma integrity protein, via the α‐dystrobrevin‐syncoilin interaction, providing a strong mechanical link between the intracellular cytoskeleton and the extracellular matrix

Dystrophin is a large protein that serves to maintain synchronous stretch and contractions by anchoring the sarcomere (via actin filaments) to the sarcolemma (via the BL) of the muscle (Hoffman, Brown, & Kunkel, 1987 ). Duchene muscular dystrophy (DMD‐d) and Becker muscular dystrophy represent two major dystrophinopathies that are caused due to mutations (frameshift in the former case) resulting in aberrant dystrophin expression causing asynchronous stretching of the sarcomere and tears in the sarcolemma (Mah et al., 2014 ). Studies in dystrophic animal models with mutated dystrophin have shown an overexpression of utrophin, a protein similar to dystrophin in structure and function probably as a compensatory mechanism for reduced dystrophin functionality (Hirst, McCullagh, & Davies, 2005 ). Dystrophin is part of a large group of proteins DAPC containing sarcoplasmic (signaling) proteins (α‐dystrobrevin, syntrophins and neuronal nitric oxide synthase [nNOS]), mechanical support proteins that are transmembrane (β‐dystroglycan, the sarcoglycans, caveolin‐3, and sarcospan) and extracellular (α‐dystroglycan and laminin; Constantin, 2014 ).

The costamere forms a critical component of striated muscle morphology connecting (or “bolting”) the sarcomeres to the sarcolemma (Peter, Cheng, Ross, Knowlton, & Chen, 2011 ). Costameres comprise of two groups of interacting proteins, both anchored on cytoskeletal F‐actin filaments, one containing the DAPC and the other containing the integrin (α7/β1) and its associated proteins talin, viniculin, and paxillin. An ankyrin‐based mechanism for sarcolemma localization of dystrophin and β‐dystroglycan has been evidenced (Ayalon, Davis, Scotland, & Bennett, 2008 ), with ankyrin‐G being required for retention of both proteins to at the costameres (Tee & Peppelenbosch, 2010 ). Spectrin‐B2 is required for the association of β‐ankyrin with dystrophin at the costameres (Ayalon et al., 2011 ). Spectrin‐B2 also interacts with MLP (Z‐disk protein; Flick & Konieczny, 2000 ). Myofibrils are exposed to, and have to withstand, both axial and lateral forces during active contraction. The IF network is responsible for maintaining fiber integrity and lateral force transmission. IFs form a sheath surrounding each myofibril at that Z‐disk and connect the transverse cytoskeletal network with the sarcolemma. Desmin (mature muscle isoform) and vimentin (immature muscle isoform) are the major proteins of IF in a healthy muscle (Paulin & Li, 2004 ). Desmin mutations are associated with forms of familial myofibrillar myopathies (Goldfarb, Vicart, Goebel, & Dalakas, 2004 ; Selcen, 2011 ) and cardiomyopathies (Harada et al., 2018 ). Smaller quantities of other IF proteins nestin/paranemin, syncolin, and synemin/desmuslin connect the IF network with edges of Z‐disk. Various plectin isoforms (PLEC, 1f, 1, 1d and 1b) have been suggested to link desmin IF (DIF) with the thin filaments, mitochondria and nucleus within muscle (Castanón, Walko, Winter, & Wiche, 2013 ). The costameres and DIF together form the transverse fixation system of muscle.

Plectin deficiency results in epidemyolysis bullosa simplex, a class of congenital diseases characterized by dermal–epidermal separation leading to skin blistering, co‐manifested in many cases by muscular dystrophy (Winter et al., 2016 ) and blistering of the gastrointestinal tract (pylori atresia; Natsuga et al., 2010 ). Mutations of proteins associated with the transverse fixation system causes a loss in sarcolemmal integrity making muscle vulnerable to stresses leading to various types of muscular dystrophies or myopathies (Jaka, Casas‐Fraile, de Munain, & Sáenz, 2015 ). In most cases, the subcellular localization of the affected protein correlates with disease severity.

8.1. Cytoskeletal signaling

Two proteins of the DAPC, syntrophin and α‐dystrobrevin, are suggested to have a signaling role over a structural one, within muscle, in the presence of dystrophin. In the absence of these proteins, nNOS (a nitric oxide synthase) is displaced from the sarcolemma to the sarcoplasm. Recent studies suggest that aberrant nNOS signaling can negatively impact three important clinical features of dystrophinopathies and sarcoglycanopathies: maintenance of muscle bulk, force generation and fatigability (Percival, Anderson, Gregorevic, Chamberlain, & Froehner, 2008 ). Likewise, nNOS overexpression studies have shown an amelioration of the dystrophic phenotype perhaps owing to the anti‐inflammatory properties of nNOS (Wehling, Spencer, & Tidball, 2001 ). Syntrophin links to ECM via dystrophin in the DAPC, and is thought to regulate kinases, ion channels and several signaling protein cascades emphasizing its role in creating signal‐transduction complexes with the DAPC (Constantin, 2014 ). Additionally, DIF has been recently relegated a regulatory role, forming a stress‐transmitting, stress‐signaling network during high stress, and is associated with stress‐mediated JNK signaling within the muscle (Palmisano et al., 2015 ).

9. MUSCLE ATROPHY AND HYPERTROPHY

A dynamic balance between the rate of synthesis and degradation of contractile proteins establishes the health of the muscle fiber. A shift in this balance leads to visible changes in composition, appearance and performance of the muscle fiber and is caused due to factors internal and external to the muscle, such as GFs, inflammation (Haddad, Zaldivar, Cooper, & Adams, 2005 ; Jackman & Kandarian, 2004 ), oxidative stress and muscle disuse (Powers, Kavazis, & McClung, 2007 ), exercise (LaPier, 1997 ), steroids (Yu et al., 2014 ), and disease (Bailey, Zheng, Hu, Price, & Mitch, 2006 ; Doucet et al., 2007 ). The major signaling pathway that regulates muscle mass and protein synthesis is the IGF1‐Akt/PKB‐mTOR signaling pathway (Schiaffino & Mammucari, 2011 ; Figure ​ Figure12). 12 ). Briefly, signaling via IGF1 begins with IGF1 ligand binding to its receptor (IGF1R), which results in the recruitment of insulin receptor substrate (IRS1). IRS1 in turn activates P13K to produce phosphatidylinositol‐3,4,5 triphosphates (PIP3) via PIP2 phosphorylation. PIP3 activates AKT proteins which primarily function to promote protein synthesis and cell growth via direct phosphorylation and activation of its downstream target mammalian target of rapamycin (mTOR). Activated mTOR complexes with protein RPTOR to form mTOR complex 1 (mTORC1), and RICTOR to form mTOR complex 2 (mTORC2). mTORC1 positively regulates the activation of its downstream targets S6K1 and negatively the inhibitor of eIF4E‐4EBP1 leading to increased protein translation and synthesis. Other downstream targets of AKT include the glycogen synthase kinase 3b (GSK3β) and forkhead box O (FOXO) transcription factors. Inhibition of GSK3β by AKT relieves inhibition of the initiation factor eIF2B increasing protein synthesis.

Schematic representation of the major receptors and signaling pathways/proteins involved in atrophy and hypertrophy. We identify only the major molecular actors within each pathway for the sake of simplicity. The IGF/AKT pathway forms a crucial pathway for hypertrophy in muscle. While activation of MURF1/Atrogin1 via the SMAD, NFκB and STAT signaling lead to atrophy

Increased activation of IGF1‐AKT‐mTOR signaling pathway is one of the main causes for increased muscle bulk, via SC activation leading to muscle hypertrophy. Clinically, hypertrophy is characterized by both an increase in myocyte number (hyperplasia) and size. Hypertrophy is characteristic of a clinically strong and healthy “exercised” muscle (e.g., in athletes) and in pathology such as myotonia congenita (Varkey & Varkey, 2003 ). In addition to the classical IGF1‐AKT‐mTOR pathway, hypertrophy in healthy muscle has been shown to be induced due to SC activation via G‐protein coupled receptors, specifically via the α‐subunit Gαi2 (Minetti et al., 2011 , 2014 ) and through myostatin inhibition (Amthor et al., 2009 ; X. Zhu, Hadhazy, Wehling, Tidball, & McNally, 2000 ). Gαi2 can bypass AKT in both a PKC‐dependent and HDAC4‐dependent manner, perturbing GSK3β and S6K1 signaling downstream of mTOR (Minetti et al., 2014 ). Recent knockdown studies of MRF4 have shown induction of muscle growth (hypertrophy) via activation of MEF2 and its downstream targets (Moretti et al., 2016 ). Aerobic exercise has been demonstrated to acutely and chronically alter protein metabolism and induce skeletal muscle hypertrophy (Konopka & Harber, 2014 ).

When the synthesis versus degradation balance shifts increasingly towards protein degradation in response to a variety of stimuli, including viral and bacterial infection, exposure to pro‐inflammatory cytokines, mitogens, GFs, and oxidative and biomechanical stresses, the muscle atrophies. Atrophying muscle is characterized by a wasting or a loss of muscle mass accompanied by a decrease in the cross‐sectional area of the muscle fiber, the muscle volume, and the amount of muscle protein (Boonyarom & Inui, 2006 ; Jackman & Kandarian, 2004 ). Muscle atrophy can occur for various reasons such as disease, injury, and extended periods of immobility (e.g., limb immobilization or even space flight). Four major proteolytic systems, namely, lysosomal (autophagic), proteasomal, calpains and caspases, become activated and contribute to atrophy depending on various environmental and cellular cues. Several studies have focused on systematically decoding the gene expression signatures for protein degradation in the atrophying muscle via the ubiquitin‐proteasome system (Bodine et al., 2001 ; Gomes, Lecker, Jagoe, Navon, & Goldberg, 2001 ; Lecker, Jagoe, Gilbert, et al., 2004 ; Sandri et al., 2004 ). Atrogin‐1 and MURF1 represent two ubiquitin E3 ligases of the ubiquitin‐proteasome system, with initiation factor eIF3f and myosin chains as main substrates, respectively (Foletta, White, Larsen, Léger, & Russell, 2011 ). They are largely considered “master regulators” of muscle atrophy (Bodine & Baehr, 2014 ). Expression of these two regulators in muscle depends on the translocation and activity of FOXO transcription factors, which are controlled via the AKT pathway (Sandri et al., 2004 ; J. Zhao et al., 2007 ). Specifically, reduced AKT activation in atrophic muscle permits phosphorylation and translocation of FOXO to the nucleus, sufficient to promote protein breakdown via the increased expression of atrogin‐1 and MURF1; while genetic activation of AKT is evidenced to be sufficient to initiate hypertrophy, it is crucial for weight recovery after atrophy (Sandri et al., 2004 ; Stitt et al., 2004 ). Myostatin, a secreted molecule of the TGFβ family acts to limit muscle growth (via the MURF1‐independent activation SMAD2/3 pathway; Sartori et al., 2009 ) in healthy muscle and is over‐expressed in certain forms of atrophies and hypertrophies (Rodriguez et al., 2014 ). Myostatin inhibition is currently being pursued as a potential therapy for certain myopathies (Y.‐S. Lee et al., 2015 ).

Pro‐inflammatory factors, particularly factors such as interleukin (IL‐1) and TNFα also upregulate the expression of the two key E3 ligases, MURF1 and atrogin‐1, signaling through two established pathways of p38MAPK (Y.‐P. Li et al., 2005 ) and NFκB (Jackman, Cornwell, Wu, & Kandarian, 2013 ) bringing about muscle atrophy. Independent activation of atrogin‐1 in the presence of a pro‐inflammatory cytokine TNFα via its action on FOXO4 (Moylan, Smith, Chambers, McLoughlin, & Reid, 2008 , p. 4) has been reported. Chronic, low‐level increase in circulating interleukin (IL‐6) is observed in several disease states and exercised muscle. IL‐6, unlike IL‐1 has been suggested to induce atrophy through a negative feedback mechanism by controlling the STAT3 phosphorylation state (and its translocation to nucleus to activate its downstream targets) contributing to a more catabolic state in the muscle (via the JAK/STAT (Haddad et al., 2005 ) pathway and in an NFκB‐dependent manner (Ma et al., 2017 )). Recent work has highlighted an amelioration of denervation‐induced atrophy by inhibiting IL‐6‐STAT3 signaling in FAPs (Madaro et al., 2018 ; Marazzi & Sassoon, 2018 ), further emphasizing the influence of immune signaling on muscle atrophy. Another ubiquitin ligase E3, FBXO40, is shown to initiate atrophy in denervated muscle ubiquitinating IRS1, thus inhibiting the downstream PI3K/AKT pathway (Ye, Zhang, Xu, Zhang, & Zhu, 2007 ). Loss of Ca 2+ homeostasis due to increased oxidative stress (Smuder, Kavazis, Hudson, Nelson, & Powers, 2010 ) or in diseases such as muscular dystrophy (Tidball & Spencer, 2000 ), can activate non‐lysosomal Ca 2+ ‐regulated proteases called calpains (R. M. Murphy, 2010 ). In muscle wasting, calpain‐3 proteolysis occurs via the AKT pathway, and is suggested to act on several cytoskeletal proteins such as titin, desmin and α‐actinin, the actomyosin complex—preferentially at the Z‐disk, contributing to atrophy and fiber necrosis (Bartoli & Richard, 2005 ; Huang & Zhu, 2016 ). Contradictory to the role of ubiquitous calpains, inactivation of calpain 3 leads to muscular dystrophy and its complete lack is associated with a type of LGMD‐2A (Saenz, Leturcq, Cobo, et al., 2005 ). Inflammatory cascades, beginning with activation of interleukins (see Section 10.1 ) acting via the NFκB signaling pathway, also lead to muscle atrophy. Caspases, a set of apoptotic enzymes, specifically caspase‐3 are overexpressed in certain atrophies of the muscle (e.g., denervation atrophy, DMD‐d) (Du, Wang, Miereles, et al., 2004 ; Sandri, El Meslemani, Sandri, et al., 2001 ).

As seen above, atrophy and hypertrophy occur as response to a variety of inflammatory stimuli, oxidative/biomechanical stresses inextricably linked to the health of muscle segueing into our next section on inflammation and oxidative stress.

10. INFLAMMATION AND OXIDATIVE STRESS

Research in the past two decades has focused extensively on a synergistic relationship between oxidative stress and inflammation, which in turn mediate several chronic diseases of muscular, neurological, nephrological and pulmonary etiology (Biswas, 2016 ; Cachofeiro et al., 2008 ; Hald & Lotharius, 2005 ), in addition to cancer (Khansari, Shakiba, & Mahmoudi, 2009 ; Reuter, Gupta, Chaturvedi, & Aggarwal, 2010 ). While oxidative stress is defined as an imbalance between production and removal of free radicals and reactive metabolites (reactive oxygen species, ROS) generated as by‐products of metabolism and catabolism, via protective mechanisms (antioxidants); inflammation is a biological response to injury with the recruitment and activation of several anti‐ and pro‐inflammatory factors (Figure ​ (Figure13). 13 ). In the following sections, we uncover the most basic mechanisms and response to inflammation and oxidative stress within skeletal muscle.

A schematic representation of the relationship between inflammation and oxidative stress—various triggers including excessive exercise or a complete lack, nutritional excess and deficits, or disease and injury greatly influences the mediators

10.1. Inflammation

Inflammatory response is a crucial biological response, which has been extensively studied in the context of skeletal muscle growth and repair, sarcopenia, and myopathies. Inflammation begins with a coordinated activation of several signaling pathways and the recruitment of pro‐/anti‐inflammatory factors such as macrophages and neutrophils to the damage site, initiating tissue repair. Neutrophils represent the most abundant immune cells recruited to the site of injury (within the first 24 hr) with numbers declining past 24 hr, with increasing recruitment of macrophages by 48 hr after injury (Tidball, 2011 ). However, the precise mechanism by which inflammatory cells are attracted to injury sites is still an active area of research. Recruited and resident immune cells of injured muscle secrete pro‐inflammatory cytokines such as IL‐1, IL‐8, IL‐6, and TNFα triggering a cascade of downstream inflammatory signaling pathways NFκB represents one of the most significant signaling molecule activated upon injury in skeletal muscle (Mourkioti & Rosenthal, 2008 ). It has long been identified to play a crucial role in atrophying and diseased muscle (e.g., inflammatory myopathies and dystrophinopathies; Jackman et al., 2013 ; H. Li, Malhotra, & Kumar, 2008 ).

Canonically, NFκB is triggered by stimulation of pro‐inflammatory factors such as the TNFα or its associated cytokines (Lawrence, 2009 ), toll‐like receptor family (TLR) and cytokine IL‐1. This triggers the activation of IKKβ leading to phosphorylation and degradation of IκB complexes. NFκB (NFκB1) liberated from IκB inhibitory proteins translocates to the nucleus leading to target gene transcription. Noncanonically, NFκB (p52/NFκB2) is activated by stabilizing NIK (NFκB inducing kinase) through the degradation of TRAF inhibitory proteins. NIK activates IKKα leading to the phosphorylation of p100 and subsequent target gene transcription via p52/RELB (Sun, 2011 ). NFκB target genes encode cytokines, chemokines, cell adhesion molecules, growth factors, and several enzymes associated with the ubiquitin‐proteasome system. For example, NFκB directly regulates cellular growth, differentiation and metabolism by regulating genes such as cyclin‐D1 (Guttridge, Albanese, Reuther, Pestell, & Baldwin, 1999 ) and MyoD (Guttridge, Mayo, Madrid, Wang, & Baldwin, 2000 ; Shintaku et al., 2016 ). NFκB increases protein turnover via MURF1 (C.‐L. Wu, Cornwell, Jackman, & Kandarian, 2014 ) and induces IL‐6 activation (Yeagley & Lang, 2010 ). Cytokines IL‐1 and TNFα are also shown to increase circulating levels of interferon‐γ, which initiates a cascade of events to clear myofiber debris, regulate regeneration (via activation of the JAK1/2‐STAT1 pathway; Doles & Olwin, 2014 ; Horvath, 2004 ) and control myogenesis (via CIITA repression of myogenin; Londhe & Davie, 2011 ). A second wave of macrophages secretes anti‐inflammatory cytokines such as IL‐10 and TGFB1 leading to an ablation in the inflammatory response (L. Arnold et al., 2007 ). More recently, the anti‐inflammatory action of IL‐10 has been shown to be mediated by a metabolic reprogramming of macrophages where IL‐10 inhibits lipopolysaccharide (LPS)‐induced glycolysis and promotes oxidative phosphorylation. IL‐10 also suppresses mTOR activity causing mitophagy and suppressed inflammasome activation (Ip, Hoshi, Shouval, Snapper, & Medzhitov, 2017 ). Under certain pathological conditions chronic activation of certain cytokines such as IL‐6 lead to deleterious effects (Muñoz‐Cánoves, Scheele, Pedersen, & Serrano, 2013 ). IL‐6 is suggested to affect insulin growth factor signaling (IGF1) and shift the balance of STAT3 via SOCS3 protein phosphorylation in favor of a more catabolic profile, promoting muscle atrophy (Haddad et al., 2005 ).

A balance between the pro‐ and anti‐inflammatory cytokines is essential to maintain muscle health with imbalances leading to deleterious effects, such as incases of chronic inflammation as seen in inflammatory myopathies (IM, polymyositis, dermatomyositis, and inclusion body myositis) (Reimers, Fleckenstein, Witt, Müller‐Felber, & Pongratz, 1993 ). These IM are clinically characterized by proximal and symmetric muscle weakness and histologically by an excess of inflammatory infiltrates. Histopathology shows evidence for necrosis, fiber size variation, and a muscle degeneration/regeneration phenotype. IMs mostly also exhibit fibrosis (Ueha, Shand, & Matsushima, 2012 ; see Section 7.1 ).

10.2. Oxidative stress

The high metabolic capacity/activity of skeletal muscle makes it susceptible to increased oxidative stress, with the cell generating ROS including peroxidases, superoxides, and hydroxyl radicals, as a byproduct of normal cellular metabolism (Powers, Ji, Kavazis, & Jackson, 2011 ). Lack of ROS homeostasis leads to cellular damage and dysfunction via its interaction with/modification of cellular macromolecules (e.g., membrane lipids, DNA, proteins and protein thiol side chains) (Berlett & Stadtman, 1997 ; Meng & Yu, 2010 ).

In normal physiology, antioxidant mechanisms maintain free radical homeostasis including release of enzymes such as superoxide dismutase, catalase, and glutathione peroxidase that scavenge ROS (Kozakowska, Pietraszek‐Gremplewicz, Jozkowicz, & Dulak, 2015 ). Oxidative stress regulates/is regulated by a host of transcription factors including NFκB (Morgan & Liu, 2011 ), p53 (Beyfuss & Hood, 2018 ), HIF‐1α (Mason & Johnson, 2007 ), leading to the expression of several GFs, inflammatory cytokines, chemokines, and cell cycle regulatory molecules. Studies have associated increasing ROS with fiber atrophy and necrosis observed in cases of severe muscle disuse (Powers, Smuder, & Judge, 2012 ), sarcopenia (Brioche & Lemoine‐Morel, 2016 ), obesity and diabetes (Haskins, Bradley, Powers, et al., 2003 ; Newsholme, Cruzat, Keane, Carlessi, & de Bittencourt, 2016 ), and muscular dystrophies (M. H. Choi, Ow, Yang, & Taneja, 2016 ; Terrill et al., 2013 ).

Oxidative stress inhibits the AKT/mTOR pathway and its downstream targets, subsequently suppressing protein synthesis and promoting atrophy (O'Loghlen, Perez‐Morgado, Salinas, & Martin, 2006 ; Tan, Shavlakadze, Grounds, & Arthur, 2015 ; L. Zhang, Kimball, Jefferson, & Shenberger, 2009 ). Alternatively, AMPK activation in response to oxidative stress also inhibits protein synthesis via mTOR1 and TSC2 phosphorylation (Y. Zhao et al., 2017 ). An autophagic response leading to atrophy can also be initiated via mTOR phosphorylation. mTOR1 activation induces the autophagosome formation by activating a required protein, the ULK1 complex (ULK1, ATG13, and FIP200), and subsequently the PI3K complex (in the presence of Ambra1) (Di Rienzo, Antonioli, Fusco, et al., 2019 ; Nazio & Cecconi, 2013 ). Superoxide or hydroxyl radicals derived from superoxides are suggested to contribute to the oxidative damage especially during reperfusion in muscle (Zweier & Talukder, 2006 ). In addition to metabolism (mitochondrial ROS production), a chronic inflammatory response can activate nicotinamide adenine dinucleotide phosphate oxidases and other inducible family of enzymes, which produce ROS, cyclically amplifying ROS and triggering further inflammation in skeletal muscle. A detailed review on the relationship between oxidative stress and autophagy is presented in Rodney, Pal, and Abo‐Zahrah ( 2016 ).

11. ENERGY METABOLISM

In addition to liver, skeletal, and cardiac muscles represent major sites for maintaining an organism's energy homeostasis. The high metabolic capacity of skeletal muscle is driven by an extensive requirement of ATP by the cross‐bridge cycle (see Section 6.2 ), required to generate force and motion. Two processes serve as the major mechanisms for muscle energy metabolism, namely, glycolysis and oxidative metabolism and are discussed in the following sections (Figure ​ (Figure14 14 ).

Schematic representation of major molecular markers involved in muscle energy metabolism—glycolysis occurs outside the mitochondrion—when a six‐carbon is converted to a 3‐carbon pyruvate molecule generating energy in the form of ATP and NADH. Pyruvate is additionally imported into the mitochondrion, where it is converted to acetyl‐CoA and enters the citric acid (TCA) cycle. Acetyl‐CoA is also generated via β‐oxidation of lipids in the mitochondria. The energy produced during TCA (NADH) is utilized by the electron transport chain, in the cristae of the mitochondria to generate three energy rich ATP molecules and water. In anaerobic glycolysis, the NADH produced is utilized for lactate production, in contrast to the OXPHOS system for ATP generation under aerobic conditions. For simplicity, the number of molecules of ATP, NADH, or NAD are not shown

11.1. Glycolytic metabolism/glycolysis

Rapid ATP requirements are catered to by metabolism of glucose either aerobically or anaerobically in the exercising muscle. Glycolytic metabolism serves as the primary source of energy, especially, in fast Type II fibers during short intense activity bursts, in a setting of limited blood flow and oxygen (hypoxia). Anaerobic glycolysis occurs in conditions of high‐intensity and sustained isometric activity (such as lifting weights; Spriet, 1992 ) with muscle shifting to an aerobic glycolysis profile during isotonic exercise (such as walking). It is well known that most cancers adopt high rates of glycolysis irrespective of oxygen abundance (Warburg effect; Vander Heiden, Cantley, & Thompson, 2009 ).

Glycolysis begins with the transport of glucose across the sarcolemma by GLUT4 (Leto & Saltiel, 2012 ). GLUT4 is an insulin‐sensitive glucose transporter, crucial for glucose uptake by skeletal muscle and is promoted by AMPK activation (Musi & Goodyear, 2003 ). AMP‐AMPK, a serine/threonine kinase, is a key modulator of skeletal muscle metabolism that controls both transcription and phosphorylation states of metabolic enzymes (Hardie, 2011 ; Jäger, Handschin, Pierre, & Spiegelman, 2007 ). AMPK, which also serves as a nutrient sensor, is activated in the muscle during reduced ATP levels, in response to intense exercise or cellular stresses (e.g., oxidative stress). Chronic AMPK activation alters metabolic gene expression and induces mitochondrial biogenesis (Bergeron et al., 2001 ; McGee et al., 2003 ).Glucose is prepared for glycolysis by the phosphorylating enzyme hexokinase (HK1). Phosphorylase (PYGM) and other debranching enzymes produce αD‐Glucose 1P from glycogen. GYS1 serves to replenish intracellular glucose from glycogen stores. The rate‐limiting step in glycolysis, however, is the conversion of fructose‐6‐phosphate to fructose‐1,6‐diphosphate by the enzyme phosphofructokinase (PFKM). The last step in anaerobic glycolysis is the conversion of pyruvate to lactate by lactate dehydrogenase (LDHA/LDHB) (and the NADH is not utilized by OXPHOS), while the pyruvate is converted to acetyl CoA via pyruvate dehydrogenase complex (PDHA, DLAT, and DLD) during aerobic glycolysis, and is utilized by the tricarboxylic acid (TCA) cycle to generate ATP in the mitochondrial matrix (see oxidative metabolism). Additional molecular markers involved in glycolysis are identified in Figure ​ Figure14 14 .

Disruption in glycogen storage and metabolism result in glycogen storage diseases of the muscle (Hers, 1964 ; Özen, 2007 ). These diseases are often associated with exercise intolerance arising from limited energy supply and excessive glycogen buildup. Though accumulation of inorganic phosphates (Pi) and ADP are known to contribute to muscle fatigue, the major player in glycogen storage diseases appear to be acidification resulting from increasing lactate concentrations (lactic acidosis) within the muscle fibers. Immediate energy requirements in the muscle are additionally met by muscle creatine kinase (CKM) which transfers high‐energy phosphates (Pi) from phosphocreatine stores, to convert the ubiquitous ADP to ATP (Baird, Graham, Baker, & Bickerstaff, 2012 ).

11.2. Oxidative metabolism

Oxidative metabolism serves as the primary source of energy production and utilizes both lipids and the products of glycolysis for satisfying sustained energy requirement through aerobic oxidation, linking it tightly to the physical activity of an organism. Breakdown of lipids in muscle occurs mainly through β‐oxidation of fatty acids (Eaton, Bartlett, & Pourfarzam, 1996 ). β‐Oxidation begins with lipids/triglycerides broken down to free fatty acids via lipin and TAG lipases. Fatty acids primarily enter the muscle cell through fatty acid transporters such as fatty acid translocases (e.g., CD36), SLC27 family of fatty acid transporters (FATP/SLC27A1) and plasma membrane bound fatty acid binding protein (e.g., FABP3). Once inside the cell, a CoA group is added to the fatty acid by fatty acyl‐CoA synthase, forming long‐chain acyl‐CoA (Berg, Tymoczko, & Stryer, 2002 ).

Mitochondrial content or volume within muscle is a major quantitative indicator of the muscle's oxidative capacity. Mitochondria consume the greatest amount (some 85–90%) of oxygen in cells to allow mitochondrial oxidative phosphorylation (OXPHOS), which is the primary metabolic pathway for ATP production (Gnaiger, 2009 ). The coupling of upstream oxidative processes (glycolysis, β‐oxidation, and TCA turnover) to OXPHOS during energy demand results in release of free energy as ATP (Kunz, 2001 ). As the first step, carnitine palmitoyltransferase 1 (CPT1) converts long‐chain acyl‐CoA to long‐chain acylcarnitine allowing fatty acid moieties to be transported across the inner mitochondrial membrane via carnitine translocase, which exchanges long‐chain acylcarnitines for carnitine. The inner mitochondrial membrane CPT2 converts long‐chain acylcarnitine back to long‐chain acyl‐CoA. The long‐chain acyl‐CoA enters the fatty acid β‐oxidation pathway, resulting in the production of acetyl‐CoA, which enters the mitochondrial TCA cycle (Berg et al., 2002 ; Wanders, Ruiter, IJlst, Waterham, & Houten, 2010 ). The NADH and FADH2 produced by both fatty acid β‐oxidation and TCA cycle are used by the electron transport chain to produce three energy‐rich ATP molecules and a water molecule, in the cristae of the mitochondria (OXPHOS) (Kunz, 2001 ). More recently, cellular localization of the mitochondrial OXPHOS system has been detected in the sarcolemma (H. Lee et al., 2016 ). Details of several molecular actors in fatty acid oxidation are provided in Figure ​ Figure14 14 .

The peroxisome proliferator‐activated receptor γ (PPARγ) and its coactivator PPARγ 1α (PGC‐1α) tightly regulate oxidative metabolism and drive the expression of several genes responsible for ATP synthesis. PGC‐1α binds to, and increases the activity of PPARs, which regulate several genes including FATP, ACS, CD36, MCAD, CPT1, and LCAD (Muoio & Koves, 2007 ). Increased activation of PGC‐1α is associated with increased mitochondrial biogenesis in the muscle (Z. Wu et al., 1999 ). PGC‐1α is controlled by AMPK, which functions to either directly affect PGC‐1α phosphorylation or activate SIRT‐1, a deacetylase which increases the activity of PGC‐1α (Cantó & Auwerx, 2009 ). The oxidative phenotype and the activation of PGC‐1α is linked to physical activity levels and beneficial effects in metabolic diseases and other pathologies (H. Liang & Ward, 2006 ). In addition to glycolysis and β‐oxidation, amino acids can supply substrates to the TCA cycle for sustained mitochondrial ATP production; for example, the amino acid, glutamine, can generate glutamate, which subsequently fuels the TCA cycle through a series of biochemical reactions termed glutaminolysis (DeBerardinis, Mancuso, Daikhin, et al., 2007 ).

11.3. Effect of exercise on metabolism

Exercise intensity (aerobic or endurance training vs. anaerobic or resistance training) determines the choice of either a glycolytic or an oxidative metabolic profile (Baker, McCormick, & Robergs, 2010 ) in fiber types. The relative contribution of carbohydrate and lipid to oxidative metabolism during exercise is further influenced by prior diet, training status, sex, and environmental conditions (Jeukendrup, 2004 ; Romijn, Coyle, Sidossis, et al., 1993 ) which in turn affect the availability of several important factors such as ATP, levels of circulating hormones (e.g., insulin), substrates, and metabolites. For instance, as mentioned earlier, PGC‐1α has been identified as a core regulator of mitochondrial biogenesis. A single bout of endurance exercise is shown to induce rapid and sustained increase of PGC‐1α (Mathai, Bonen, Benton, Robinson, & Graham, 2008 ) with improvements to whole‐body oxygenation (peak oxygen uptake), and a shift from carbohydrate to fat substrates (Calvo et al., 2008 ). Overexpression studies of PGC‐1α have also shown large increases in functional mitochondrial and genetic programs characteristic of slow‐twitch fibers resistant to contraction‐induced fatigue (Lin et al., 2002 ). Knockout of PGC‐1α in mice models was shown to cause a shift in fiber types from oxidative Type I and IIA to Types IIX and IIB. These animals also exhibited reduced endurance capacity and increased fiber damage, further emphasizing the role of PC‐1α in maintaining muscle fiber integrity and energy homeostasis (Handschin et al., 2007 ).

Utilization of carbohydrate substrates increase with increasing exercise intensity, coupled with reduced lipid oxidation. It is suggested that carnitine, which is essential for CPT1 regulation, serves as the regulatory candidate for fatty acid oxidation in muscle. As exercise intensity increases, the level of free carnitine fall reducing CPT1 activity and inhibiting β‐oxidation (Jeppesen & Kiens, 2012 ). Exercise training, its intensity, duration, and glucose supply, have been shown to be factors regulating GLUT4 (regulated by AMPK) translocation and activity. Regulation of GLUT4 contributes to improved insulin action, glucose disposal and enhanced muscle glycogen storage following exercise (reviewed in Richter & Hargreaves, 2013 ). The interaction between fat and carbohydrate metabolism in exercise is further reviewed in Spriet ( 2014 ).

11.4. Immunometabolism—A synergistic relationship between immunity and metabolism

Skeletal muscle serves as the major site for insulin‐stimulated glucose disposal and subsequently, glucose homeostasis. Association of metabolic and cardiovascular diseases with exercise and muscle metabolism are widely acknowledged. Several of these diseases also exhibit chronic tissue inflammation with obesity, as an underlying etiology. Recent research has begun to unravel the complexity of this cross‐talk (both inter‐ and intra‐organ) between inflammation and metabolism, spawning a body of active and rapidly expanding research called “immunometabolism” (Hotamisligil, 2017a ). In the following section, we highlight several important factors that have been identified as contributing to immunometabolism within skeletal muscle. We do not focus on a whole‐body view (intra‐organ) signaling that drives communication between immune and metabolic factors (Hamrick, 2011 , 2012 ; Y. S. Lee, Wollam, & Olefsky, 2018 ).

Skeletal muscle, in states such as exercise, injury, inactivity or disease, is replete with infiltrating immune cells (e.g., macrophages, Pillon & Krook, 2017 ), and circulating immune factors (cytokines and adipokines derived from muscle fat depots—intermyocellular and perimuscular adipose tissue; Khan et al., 2015 ). Additionally, it is also now established that the skeletal muscle is an endocrine organ secreting cytokines and other peptides (such as IL‐6, IL‐8, IL‐15, IGF1, FGF21, FSTL1, irisin, all termed “myokines”), whose levels are regulated by muscle contractile activity (Febbraio & Pedersen, 2005 ; Pedersen, 2011 ; Schnyder & Handschin, 2015 ) and subsequently exercise (So, Kim, Kim, & Song, 2014 , p. 201). Interestingly, several of these are known to be secreted by adipocytes and are often referred to in literature as adipomyokines (Raschke & Eckel, 2013 ). For instance, irisin, a recently discovered and much debated exercise (PGC‐1α) induced myokine (Albrecht et al., 2015 ; Panati, Suneetha, & Narala, 2016 ) is suggested to be a metabolic regulator in muscle (Blizzard LeBlanc, Rioux, Pelech, et al., 2017 ; Perakakis et al., 2017 ). A detailed review on role of exercise in influencing the action of several myokines mentioned here, and the cross‐talk between muscle and adipose tissues are presented in Stanford and Goodyear ( 2018 ). These cytokines/myokines exert auto‐, para‐ and/or endocrine effects in a context‐specific manner enabling muscle to maintain the metabolic homeostasis of lipids and proteins, in health and exercise (C. Brandt & Pedersen, 2010 ; Pedersen, Akerstrom, Nielsen, & Fischer, 2007 ; Figure ​ Figure15 15 ).

Schematic representation of the key signaling molecules in immunometabolism. The cross‐talk between metabolic and inflammatory signaling pathways occurs at multiple levels (inter‐ and intra‐tissue/organ). Several of the above shown factors are part of the skeletal muscle secretome (myokines; adipomyokines) such as IL‐15 a regulator of muscle adiposity, IL‐6 crucial for inflammation and glucose homeostasis; and several fat/ glucose metabolic genes (AMPK, FGF21, IGF1,PGC1α, Irisin) that play a pivotal role in maintaining the immunometabolic profile of skeletal muscle

A shift in balance from an immunometabolic adaptive profile, observed in healthy muscle tissue, to a maladaptive state as observed in chronic metabolic disorders (obesity, Ray, Mahata, & De, 2016 and T2DM), occurs through deficient cross‐talk between immune and metabolic signaling factors such as the inflammasome (Próchnicki & Latz, 2017 ), insulin receptors (Hotamisligil, 2017b ), TNFα (Austin, Rune, Bouzakri, Zierath, & Krook, 2008 ; Hotamisligil, Shargill, & Spiegelman, 1993 ), and other cytokines (Fink, Oberbach, Costford, et al., 2013 ; Pillon & Krook, 2017 ).

For instance, elevation in circulating TNFα levels (observed in tissues such as adipose (Hotamisligil et al., 1993 ) and muscle (Saghizadeh, Ong, Garvey, Henry, & Kern, 1996 )) causes a downstream activation of stress kinases, triggering TNF‐mediated insulin resistance and glucose dyshomeostasis (reviewed in Hotamisligil, 2017b ).

IL‐6 is shown to have acute insulin‐like effects (Carey et al., 2006 ; Ellingsgaard et al., 2011 ; Pedersen & Febbraio, 2008 ) in healthy muscle, which do not persist under chronic conditions. IL‐6 enhances glucose uptake and translocation of the glucose transporter GLUT4, enhancing insulin‐stimulated glucose uptake (Carey et al., 2006 ) while chronically elevated IL‐6 has been shown impair insulin‐stimulated glucose uptake in muscles (Franckhauser, Elias, Sopasakis, et al., 2008 ). Circulating IL‐6 is also known to exert anti‐inflammatory effects in the context of exercise. Elevation of IL‐6 during exercise induces an anti‐inflammatory environment by inducing the production of IL‐1ra and IL‐10, and also inhibiting TNF‐α production; subsequently abating the chronic systemic low‐grade inflammation seen in cardiovascular disease, Type 2 diabeters, and muscle wasting (Pedersen & Febbraio, 2008 ). IL‐15 a circulating, exercise‐induced myokine has been shown to inhibit adipose tissue deposition (Quinn & Anderson, 2011 ; Quinn, Anderson, Strait‐Bodey, Stroud, & Argilés, 2009 ) and influence accumulation of fat and regulation of adiposity in muscle during inactivity (Pedersen & Febbraio, 2012 ). Other mechanisms that contribute to lipid‐induced modulation of insulin resistance (in vitro) have also been identified, such as stimulation of TLR4 (a classical innate immune surface receptor) which switches muscle metabolism to glycolysis (via LPS), inducing insulin resistance (H. Liang, Hussey, Sanchez‐Avila, Tantiwong, & Musi, 2013 ).

Metabolism within the factors associated with immunity, also affects their expression and function. For instance, metabolite profiling of activated macrophages has shown that accumulation of Kreb's cycle intermediates which are important for production of inflammatory cytokines (Jha et al., 2015 ). Macrophage polarization been shown to be affected by nutrient sensing pathways such as AMPK and mTOR1. Macrophages lacking a catalytic AMPK subunit (AMPKa1) are shown to have defective M2 polarization (Mounier et al., 2009 ). Constitutive mTOR1 activation has also been shown to result in defective M2 polarization, resulting in an enhanced pro‐inflammatory response to LPS (Byles et al., 2013 ). These mechanisms highlight the complex and yet to be fully understood interactions between immune and metabolic factors driving muscle heath.

12. SKELETAL MUSCLE CIRCULATION

Skeletal muscle accounts for ~40% of the total body weight while accounting for ~25% of the cardiac output to meet basal metabolic needs. The interested reader is directed to Korthuis ( 2011 ), for a detailed overview of skeletal muscle circulation. Briefly, anatomically, skeletal muscle is oxygenated and deoxygenated by an elaborate network of arteries and veins, respectively, whose density varies between muscle types. The arteries divide further into a network of smaller arteries (called arterioles) which penetrate the perimysium, arranged perpendicular to the muscle fiber axis branching terminally into a fine mesh of capillaries. This network joins with the network of venules and veins, giving rise to a rich lattice of vasculature enmeshing bundles of muscle fibers. Vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and pericytes represent major cell types of the vascular walls. As the energy requirements vary across muscle types, so does the density of vasculature and thickness of capillaries to cater to its oxygen demand. Blood flow is also largely regulated by alterations in vascular resistance and blood viscosity. Vascular resistance (vasoconstriction) depends on the contraction of VSMCs, triggered by the availability of cytoplasmic free Ca 2+ . Free Ca 2+ triggers formation of the Ca 2+ ‐calmodulin complex, which in turn activate myosin light chain kinase, a CaMK, that phosphorylates myosin light chains, bringing about smooth muscle contraction. Ca 2+ sensitization of the contractile proteins is signaled by the RhoA/Rho kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase (MLCP), maintaining force generation. Removal of Ca 2+ from the cytosol and stimulation of MLCP initiates smooth muscle relaxation (Webb, 2003 ).

A host of molecular factors have been identified to modulate free Ca 2+ concentration: calcium‐gated and permeable channels (Ghosh et al., 2017 ) such as CACN1C (Cav1.2), CACNA1G (Cav3.1), CACNA1H (Cav3.2), CACNA1L (Cav3.3); potassium channels (Jackson, 2005 , 2018 ) such as KCNA5 (KV1.5), KCNA6 (KV1.6), KCNJ8 (KIR6.1), KCNJ2 (KIR2.1), KCNMA1 (Slo1); and EC‐derived factors (Kedzierski & Yanagisawa, 2001 ) such as endothelium‐derived hyperpolarizing factor, endothelin (a vasoconstrictor), and vasodilators such as NO, CO, and H 2 S.

Skeletal muscle research has focused extensively on the role of nitric oxide (NO) in vasodilation (McConell, Rattigan, Lee‐Young, Wadley, & Merry, 2012 ) and in response to exercise and injury (Hong, Betik, & McConell, 2014 ; McConell et al., 2012 ; Stamler & Meissner, 2001 ). NOS/cyclic guanosine monophosphate (cGMP)‐induced relaxation is shown to correlate with MLCP phosphorylation (Francis, Busch, & Corbin, 2010 ; Nakamura, Koga, Sakai, Homma, & Ikebe, 2007 ). Neuronal and endothelial nitric oxide synthase (nNOS/NOS2 and eNOS/NOS3) represent major muscle‐specific synthases that are activated by the interaction between Ca 2+ and calmodulin. NO diffuses into VSMCs to activate guanylyl cyclase which results in the production of cGMP (Kobzik, Reid, Bredt, & Stamler, 1994 ) and a subsequent activation of protein kinase G, resulting in vasodilation. With dynamic exercise, there is considerable remodeling of the vascular system (Green, Spence, Rowley, Thijssen, & Naylor, 2012 ) driven by NO and VEGF (Hoier & Hellsten, 2014 ). VEGF represents an important class of angiogenic factors that affect and influence skeletal muscle circulation as detailed below.

12.1. Vascular endothelial growth factor signaling

Vascular endothelial growth factor A (VEGFA), with nine known isoforms, is the major regulator of vasculature development during embryogenesis (vasculogenesis) (Ferrara et al., 1996 ) and a potent inducer of neovascularization in adult tissue (angiogenesis) (Patan, 2004 ). VEGFA stimulates angiogenesis by promoting EC migration, proliferation and differentiation to form new vessel structures. VEGF induces DLL4, which functions to pattern the endothelial population into tip and stalk cells. VEGFA also serves as an angiogenic stimulus guiding tip cells through the ECM. Tip cells, enriched with VEGFA receptors (VEGFR2) sense and align spatially along the VEGFA gradient, thus providing a map for alignment of proliferating stalk cells to form capillaries (Gerhardt, 2008 ). Sufficient oxygen perfusion into the muscle upon capillary formation and maturation normalizes VEGFA levels. VEGF driven angiogenesis is heavily regulated by the expression of two of its receptors—VEGFR1 and VEGFR2 (Olsson, Dimberg, Kreuger, & Claesson‐Welsh, 2006 ).

VEGFR2 mediates most of the endothelial growth and survival signals and contributes to re‐organization of the cytoskeleton by phosphorylating FAK (focal adhesion kinase) and paxillin, while VEGFR1, an early inhibitor of angiogenesis plays an important role in disease, progression and management (Amano, Kato, Ito, et al., 2015 ; Hiratsuka et al., 2001 ; Jain, 2005 ). Interaction between VEGFR1 and VEGFR2, regulated by placental growth factor has been identified and suggested to amplify VEGFA‐driven angiogenesis (Autiero, Waltenberger, Communi, et al., 2003 ; Autiero, Luttun, Tjwa, & Carmeliet, 2003 ). Recent research suggests that VEGFR1 predominantly modulates VEGF activity and subsequently EC homeostasis by forming heterodimers with VEGFR2 (Cudmore et al., 2012 ). In addition to ECs, SCs and differentiating myoblasts also generate VEGFA in the muscle (R. S. Williams & Annex, 2004 ). Regenerating muscle is characterized by increased capillarization. It has been suggested that the increased expression of VEGFA and its receptors, in regenerating muscle promotes growth and fusion of myofibers and SC activation leading to a more rapid regeneration enabled via several mechanisms including activation of MAPK, PI3K/AKT pathways and SC activation (Arsic et al., 2004 ).

A bidirectional, reciprocal relationship between ECs and SCs is suggested to exist within the stem cell niche. In co‐culture experiments, ECs were found to promote myoblast proliferation by secreting a panel of GFs, such as IGF‐I, HGF, FGF, PDGF, and VEGF (Christov et al., 2007 ). Contrastingly, VEGFA was shown to promote re‐entry of SCs into quiescence. SCs in the proximity of pericytes and capillaries allow for angiopoietin‐1 binding on their TIE2 receptors, simultaneously stabilizing vessels and promoting SC quiescence through the ERK1/2 pathway. Based on these observations, it has been proposed that during muscle regeneration, ECs and SCs interact with each other promoting myo‐angiogenesis (Abou‐Khalil, Mounier, & Chazaud, 2010 ; Mounier, Chrétien, & Chazaud, 2011 ).

13. COMMON MOLECULAR MECHANISMS UNDERLYING MUSCLE DISEASES

We have integrated in each section on muscle function, specific diseases that arise from genetic mutations and from aberrant functional pathways, including their clinical characteristics where appropriate (italicized); this is catalogued in Supplementary Table 2 . In addition, we recently explored common and unique aspects of muscle disorders using transcriptional profiles and a systems biology approach (Mukund & Subramaniam, 2017 ; Figure ​ Figure16). 16 ). Our analysis revealed that a majority of muscle diseases share a few common mechanisms. Across the 20 muscle diseases in our study, we identified deficient bioenergetics and a lack of Ca 2+ homeostasis as aberrant mechanistic signatures underlying muscle pathophysiology. Recent research in muscular degeneration (muscular dystrophies, Ramadasan‐Nair et al., 2014 ; cardiomyopathies, Wallace, 2000 ; and neuromuscular diseases such as ALS, Cozzolino & Carrì, 2012 ; Dupuis & Loeffler, 2009 ) have all identified mitochondrial dysfunction as a cause underlying the disease. Bioenergetics pathway enzymes have also recently been shown to be relevant biomarkers for muscular disease progression (Santacatterina et al., 2015 ).

Extracting significant disease similarities from 20 diseases affecting muscle—above figure shows the hierarchical clustering dendrogram of disease correlation. Colors on the tree indicate the clusters/grouping of diseases, while the red line indicates the threshold used for clustering. (Reprinted with permission from Mukund and Subramaniam ( 2017 ). Copyright 2017 Frontiers Publication)

Reduced efficiency in the action of the TCA cycle has been also assessed in diseased muscle associated with inflammatory myopathies (Coley et al., 2012 ), and muscular dystrophy (Even, Decrouy, & Chinet, 1994 ). Reduced ATP availability, contributing to suppressed muscle regeneration and an altered Ca 2+ homeostasis are suggested to be pivotal to muscle wasting observed in certain dystrophies such as DMD‐d (Timpani, Hayes, & Rybalka, 2015 ). Ca 2+ homeostasis in muscle determines its integrity and function, regulated mainly by SERCA pumps and RYRs. Work from our laboratory has previously identified strong dysregulation of these proteins in ALS and DMD‐d (Mukund & Subramaniam, 2015 ; Y. Wang, Winters, & Subramaniam, 2012 ). Likewise, regulation of genes regulating the action of these proteins such as ASPH (regulator of RYRs) and SLN have also been observed in muscle from cerebral palsy, a neuromuscular disease (Smith, Lee, Ward, Chambers, & Lieber, 2011 ).

Several of these debilitating muscle diseases often exhibit muscle atrophy, hypertrophy and fibrosis, occurring in various combinations and to varying degrees of severity (as discussed in Sections 8.1 and 10 ). Interestingly, however, muscle, upon injury or insult, begins to express a plethora of mixed fiber and immature muscle isoforms including myosins, actins, and members of the Ca 2+ homeostasis machinery across diseases (Mukund et al., 2014 ), particularly dystrophies (reviewed in Beedle, 2016 ) and neuromuscular diseases such as ALS (Y. Wang et al., 2012 ). Cardiac muscle research suggests that activation of fetal isoforms in failing heart (cardiac muscle) confers an initial protective effect on heart function. However, precise consequences of present or persistent immature/mixed isoforms expression in skeletal muscle pathophysiology are not yet understood and offer exciting avenues for future research.

14. CONCLUSION

Human skeletal muscle is often characterized as a mechanical device responsible for generating contraction, force, and movement. Over the past decades, a detailed molecular picture of the skeletal muscle has begun to emerge, where each molecular player is associated with a “functional component” of the muscle. While some of these functional components, such as the contractile machinery or the sensing apparatus at the NMJ have received significant attention, a detailed mapping of known molecular components and their relationship to muscle function has not yet been broadly reviewed. This review is aimed at highlighting molecular components of the muscle, and the complex molecular cross‐talk with its various interacting partners (e.g., immune infiltrates, fibroblasts, adipocytes, nerve cells, ECs, environmental stressors) influencing and contributing to the health and activity of muscle tissue.

Given the breadth of muscle research, we acknowledge that thoroughly outlining every significant contribution within each of the components described here is a massive undertaking and not currently within the scope of this article. However, the comprehensive systems‐level molecular and functional pathway perspectives provided in this review, attempt to introduce the reader to important mechanisms in muscle that not only pave the way for a deeper analysis of muscle function in health and disease, but provide interesting insights into the molecular machinery that is core to muscle function. The adaptability of skeletal muscle as it attempts to revert into a precursor‐like state in response to insult or injury, as witnessed through the increased expression of fetal gene isoforms warrants further research. The contextual mechanisms described here in, also provide the basis for further investigations on the precision and limitations of pharmacological interventions.

CONFLICT OF INTEREST

The authors have declared no conflicts of interest for this article.

RELATED WIREs ARTICLES

https://doi.org/doi: 10.1002/wsbm.1184

https://doi.org/doi: 10.1002/wsbm.1197

Supporting information

Supplementary Table 1 . This table presents a list of genes (which have been referred to in the manuscript using their commonly used names) and their corresponding NCBI isoform gene symbol, relevant to our manuscript.

ACKNOWLEDGMENTS

We thank Drs Richard Lieber and Charles Burant for a careful reading of this review and their encouragement.

Mukund K, Subramaniam S. Skeletal muscle: A review of molecular structure and function, in health and disease . WIREs Syst Biol Med . 2020; 12 :e1462 10.1002/wsbm.1462 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

Funding information National Institutes of Health, Grant/Award Numbers: R01 DK109365, R01 HD084633, R01 HL106579, R01 HL108735, R01 LM012595, U01 CA198941, U01 CA200147, U01 DK097430, U19 AI090023, U2C DK119886; National Science Foundation, Grant/Award Number: STC‐0939370

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8.4: Muscle Contraction

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• Page ID 64632

• Suzanne Wakim & Mandeep Grewal
• Butte College

Arm Wrestling

A sport like arm-wrestling depends on muscle contractions. Arm wrestlers must contract muscles in their hands and arms and keep them contracted to resist their opponent's opposing force. The wrestler whose muscles can contract with greater force wins the match.

Muscle Contraction

How a skeletal muscle contraction begins.

Excluding reflexes, all skeletal muscle contractions occur as a result of conscious effort originating in the brain. The brain sends electrochemical signals through the somatic nervous system to motor neurons that innervate muscle fibers (to review how the brain and neurons function, see the chapter Nervous System ) . A single motor neuron with multiple axon terminals can innervate multiple muscle fibers, thereby causing them to contract at the same time. The connection between a motor neuron axon terminal and a muscle fiber occurs at a neuromuscular junction site . This is a chemical synapse where a motor neuron transmits a signal to muscle fiber to initiate a muscle contraction.

The process by which a signal is transmitted at a neuromuscular junction is illustrated in Figure \(\PageIndex{2}\). The sequence of events begins when an action potential is initiated in the cell body of a motor neuron, and the action potential is propagated along the neuron’s axon to the neuromuscular junction. Once the action potential reaches the end of the axon terminal, it causes the neurotransmitter acetylcholine (ACh) from synaptic vesicles in the axon terminal. The ACh molecules diffuse across the synaptic cleft and bind to the muscle fiber receptors, thereby initiating a muscle contraction. Muscle contraction is initiated with the depolarization of the sarcolemma caused by the sodium ions' entrance through the sodium channels associated with the ACh receptors.

Things happen very quickly in the world of excitable membranes (think about how quickly you can snap your fingers as soon as you decide to do it). Immediately following depolarization of the membrane, it repolarizes, re-establishing the negative membrane potential. Meanwhile, the ACh in the synaptic cleft is degraded by the enzyme acetylcholinesterase (AChE). The ACh cannot rebind to a receptor and reopen its channel, which would cause unwanted extended muscle excitation and contraction.

Propagation of an action potential along the sarcolemma enters the T-tubules . For the action potential to reach the membrane of the Sarcoplasmic Reticulum (SR), there are periodic invaginations in the sarcolemma, called T-tubules (“T” stands for “transverse”). The arrangement of a T-tubule with the membranes of SR on either side is called a triad (Figure \(\PageIndex{3}\)). The triad surrounds the cylindrical structure called a myofibril , which contains actin and myosin. The T-tubules carry the action potential into the interior of the cell, which triggers the opening of calcium channels in the membrane of the adjacent SR, causing \(\text{Ca}^{++}\) to diffuse out of the SR and into the sarcoplasm. It is the arrival of \(\text{Ca}^{++}\) in the sarcoplasm that initiates contraction of the muscle fiber by its contractile units, or sarcomeres.

Excitation-contraction coupling

Although the term excitation-contraction coupling confuses or scares some students, it comes down to this: for a skeletal muscle fiber to contract, its membrane must first be “excited”—in other words, it must be stimulated to fire an action potential. The muscle fiber action potential, which sweeps along the sarcolemma as a wave, is “coupled” to the actual contraction through the release of calcium ions (\(\text{Ca}^{++}\)) from the SR. Once released, the \(\text{Ca}^{++}\) interacts with the shielding proteins, troponin and tropomyosin complex, forcing them to move aside so that the actin-binding sites are available for attachment by myosin heads. The myosin then pulls the actin filaments toward the center, shortening the muscle fiber.

In skeletal muscle, this sequence begins with signals from the somatic motor division of the nervous system. In other words, the “excitation” step in skeletal muscles is always triggered by signaling from the nervous system.

Sliding Filament Theory of Muscle Contraction

Once the muscle fiber is stimulated by the motor neuron, actin, and myosin protein filaments within the skeletal muscle fiber slide past each other to produce a contraction. The sliding filament theory is the most widely accepted explanation for how this occurs. According to this theory, muscle contraction is a cycle of molecular events in which thick myosin filaments repeatedly attach to and pull on thin actin filaments, so they slide over one another. The actin filaments are attached to Z discs, each of which marks the end of a sarcomere. The sliding of the filaments pulls the Z discs of a sarcomere closer together, thus shortening the sarcomere. As this occurs, the muscle contracts.

Crossbridge Cycling

Crossbridge cycling is a sequence of molecular events that underlies the sliding filament theory. There are many projections from the thick myosin filaments, each of which consists of two myosin heads (you can see the projections and heads in Figures \(\PageIndex{5}\) and \(\PageIndex{3}\)). Each myosin head has binding sites for ATP (or ATP hydrolysis products: ADP and P i ) and actin. The thin actin filaments also have binding sites for the myosin heads—a cross-bridge forms when a myosin head binds with an actin filament.

The process of cross-bridge cycling is shown in Figure \(\PageIndex{6}\). A cross-bridge cycle begins when the myosin head binds to an actin filament. ADP and P i are also bound to the myosin head at this stage. Next, a power stroke moves the actin filament inward toward the sarcomere center, thereby shortening the sarcomere. At the end of the power stroke, ADP and P i are released from the myosin head, leaving the myosin head attached to the thin filament until another ATP binds to the myosin head. When ATP binds to the myosin head, it causes the myosin head to detach from the actin filament. ATP is again split into ADP and P i and the energy released is used to move the myosin head into a "cocked" position. Once in this position, the myosin head can bind to the actin filament again, and another cross-bridge cycle begins.

Feature: Human Biology in the News

Interesting and hopeful basic research on muscle contraction is often in the news because muscle contractions are involved in so many different body processes and disorders, including heart failure and stroke.

• Heart failure is a chronic condition in which cardiac muscle cells cannot contract forcefully enough to keep body cells adequately supplied with oxygen. In 2016, researchers at the University of Texas Southwestern Medical Center identified a potential new target for developing drugs to increase the strength of cardiac muscle contractions in patients with heart failure. The UT researchers found a previously unidentified protein involved in muscle contraction. The minimal protein turns off the “brake” on the heart, so it pumps blood more vigorously. At the molecular level, the protein affects the calcium-ion pump that controls muscle contraction. This result is likely to lead to searches for additional such proteins.
• A stroke occurs when a blood clot lodges in an artery in the brain and cuts off blood flow to part of the brain. Damage from the clot would be reduced if the smooth muscles lining brain arteries relaxed following a stroke because the arteries would dilate and allow greater blood flow to the brain. In a recent study undertaken at the Yale University School of Medicine, researchers determined that the muscles lining blood vessels in the brain actually contract after a stroke. This constricts the vessels, reduces blood flow to the brain, and appears to contribute to permanent brain damage. The hopeful takeaway of this finding is that it suggests a new target for stroke therapy.
• What is skeletal muscle contraction?
• Distinguish between isometric and isotonic contractions of skeletal muscle.
• How does a motor neuron stimulate a skeletal muscle contraction?
• What is the sliding filament theory?
• Describe cross-bridge cycling.
• Where does the ATP needed for a muscle contraction come from?
• Explain why an action potential in a single motor neuron can cause multiple muscle fibers to contract.
• The name of the synapse between a motor neuron and a muscle fiber is the _______________ _________.
• If a drug blocks the acetylcholine receptors on muscle fibers, what do you think this would do to muscle contraction? Explain your answer.
• True or False: According to the sliding filament theory, actin filaments actively attach to and pull on myosin filaments.
• True or False: When a motor neuron produces an action potential, the sarcomeres in the muscle fiber that it innervates become shorter as a result.
• Explain how cross-bridge cycling and sliding filament theory are related to each other.
• When does anaerobic respiration typically occur in human muscle cells?
• If there were no ATP available in a muscle, how would this affect cross-bridge cycling? What would this do to muscle contraction?

Explore More

Attributions.

• Arm wrestling by U.S. Navy photo by Lt. Kenneth Honek, public domain via Wikimedia Commons
• Motor End Plate and Innervation by OpenStax , CC BY 4.0 via Wikimedia Commons
• Skeletal muscle by Blausen.com staff (2014). " Medical gallery of Blausen Medical 2014 ". WikiJournal of Medicine 1 (2). DOI : 10.15347/wjm/2014.010 . ISSN 2002-4436 . licensed CC BY 3.0 via Wikimedia Commons
• Actin-tropomyosin-troponin by Daniel Walsh and Alan Sved, CC BY 4.0 via Wikimedia Commons
• Sliding filament model by OpenStax , CC BY 4.0 via Wikimedia Commons
• Crossbridge cycling by OpenStax , CC BY 4.0 via Wikimedia Commons
• Text adapted from Human Biology by CK-12 licensed CC BY-NC 3.0

Want to create or adapt books like this? Learn more about how Pressbooks supports open publishing practices.

109 12.1 Case Study: Muscles and Movement

Created by CK-12 Foundation/Adapted by Christine Miller

Case Study: Needing to Relax

This dog (Figure 12.1.1) is expressing his interest in something — perhaps a piece of food — by using the neck muscles to tilt its head in an adorable fashion. Humans also sometimes tilt their heads to express interest. But imagine how disturbing and painful it would be if your neck tilted involuntarily, without you being able to control it! Forty-three year old Edward unfortunately knows just how debilitating this can be.

Edward has a rare condition called cervical dystonia , which is also called spasmodic torticollis. In this condition, the muscles in the neck contract involuntarily, often causing the person’s head to twist to one side. Figure 12.1.2 shows one type of abnormal head positioning that can be caused by cervical dystonia. The muscles may contract in a sustained fashion, holding the head and neck in one position, or they may spasm repeatedly, causing jerky movements of the head and neck.

Cervical dystonia is painful and can significantly interfere with a person’s ability to carry out their usual daily activities. In Edward’s case, he can no longer drive a car, because his uncontrollable head and neck movements and abnormal head positioning prevent him from navigating the road safely. He also has severe neck and shoulder pain much of the time.

Although it can be caused by an injury, there is no known cause of cervical dystonia — and there is also no cure. Fortunately for Edward, and others who suffer from cervical dystonia,  there is a treatment that can significantly reduce symptoms in many people. You may be surprised to learn that this treatment is the same substance which, when injected into the face, is used for cosmetic purposes to reduce wrinkles!

The substance is botulinum toxin, one preparation of which may be familiar to you by its brand name — Botox . It is a neurotoxin produced by the bacterium  Clostridium botulinum , and can cause a life-threatening illness called botulism . However, when injected in very small amounts by a skilled medical professional, botulinum toxins have some safe and effective uses. In addition to cervical dystonia, botulinum toxins can be used to treat other disorders involving the muscular system, such as strabismus (misalignment of the eyes); eye twitches; excessive muscle contraction due to neurological conditions like cerebral palsy; and even overactive bladder.

Botulinum toxin has its effect on the muscular system by inhibiting muscle contractions. When used to treat wrinkles, it relaxes the muscles of the face, lessening the appearance of wrinkles. When used to treat cervical dystonia and other disorders involving excessive muscle contraction, it reduces the abnormal contractions.

In this chapter, you will learn about the muscles of the body, how they contract to produce movements and carry out their functions, and some disorders that affect the muscular system. At the end of the chapter, you will find out if botulinum toxin helped relieve Edward’s cervical dystonia, and how this toxin works to inhibit muscle contraction.

Chapter Overview: Muscular System

In this chapter, you will learn about the muscular system, which carries out both voluntary body movements and involuntary contractions of internal organs and structures. Specifically, you will learn about:

• The different types of muscle tissue — skeletal, cardiac, and smooth muscle — and their different characteristics and functions.
• How muscle cells are specialized to contract and cause voluntary and involuntary movements.
• The ways in which muscle contraction is controlled.
• How skeletal muscles can grow or shrink, causing changes in strength.
• The structure and organization of skeletal muscles, including the different types of muscle fibres, and how actin and myosin filaments move across each other — according to the sliding filament theory — to cause muscle contraction.
• Cardiac muscle tissue in the heart that contracts to pump blood through the body.
• Smooth muscle tissue that makes up internal organs and structures, such as the digestive system, blood vessels, and uterus.
• The physical and mental health benefits of aerobic and anaerobic exercise, such as running and weight lifting.
• How individuals vary in their response to exercise.
• Disorders of the muscular system, including musculoskeletal disorders (such as strains and carpal tunnel syndrome) and neuromuscular disorders (such as muscular dystrophy, myasthenia gravis, and Parkinson’s disease).

As you read the chapter, think about the following questions:

• How is the contraction of skeletal muscles controlled?
• Botulinum toxin works on the cellular and molecular level to inhibit muscle contraction. Based on what you learn about how muscle contraction works, can you think of some ways it could potentially be inhibited?
• What is one disorder involving a lack of sufficient muscle contraction? Why does it occur?

Attributions

Figure 12.1.1

Whiskey’s 2nd Birthday by Kelly Hunter on Flickr is used under a CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/) license.

Figure 12.1.2

1024px-Dystonia2010 by James Heilman, MD on Wikimedia Commons is used under a  CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) license.

Botulism [online article]. (2018, January 10). World Health Organization (WHO). https://www.who.int/news-room/fact-sheets/detail/botulism

Mayo Clinic Staff. (n.d.) Cervical dystonia [online article]. MayoClinic.org. https://www.mayoclinic.org/diseases-conditions/cervical-dystonia/symptoms-causes/syc-20354123

A drug prepared from the bacterial toxin botulin, used medically to treat certain muscular conditions and cosmetically to remove wrinkles by temporarily paralyzing facial muscles.

A soft tissue that composes muscles in animal bodies, and gives rise to muscles' ability to contract. This is opposed to other components or tissues in muscle such as tendons or perimysium.

Actions which take place according to the one's desire or are under control.

Actions which are not under one's conscious control.

Voluntary, striated muscle that is attached to bones of the skeleton and helps the body move.

Involuntary, striated muscle found only in the walls of the heart; also called myocardium.

An involuntary, nonstriated muscle that is found in the walls of internal organs such as the stomach.

Human Biology Copyright © 2020 by Christine Miller is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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The Biology Corner

Biology Teaching Resources

Case Study – The Tired Swimmer

This case study was modified from the National Center for Case Study Teaching in Science so that it is more appropriate for basic high school students in anatomy and physiology.   

This case is intended to be used during the chapter on muscles as it requires students to examine how the neurotransmitter, acetylcholine is used to trigger and muscle contraction.   

In this case, the subject is eventually diagnosed with myasthenia gravis .

Students must define basic vocabulary words that may be unfamiliar to them and label a diagram of the neuromuscular junction.    They are also introduced to the concept of autoimmune diseases which will be a common theme throughout the basic anatomy course.

The activity encourages students to use resources, like their textbook and google to help them solve the case and propose treatments for the patient.

HS-LS1-2 Develop and use a model to illustrate the hierarchical organization of interacting systems that provide specific functions within multicellular organisms

Shannan Muskopf

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All or Nothing

A Case Study in Muscle Contraction

By Ryan T. Neumann, Collin J. Quinn, Brittany A. Whitaker, Sean T. Woyton, Breanna N. Harris

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In this interrupted case study, students pose as an intern of a neuromuscular/skeletal specialist and discover how sarin and myasthenia gravis influence muscle function. Students are given background information about the patients and their situations, as well as results from blood tests. Students are asked incremental questions that build on each other with the end goal of students describing the process of muscle contraction, from motor neuron to sarcomere shortening, and learning what happens when parts of that process are disrupted. This activity was developed for use in a physiology course where the majority of the students were pre-medical, pre-nursing, or other allied health majors.

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Date Posted

• Explain the relationship that exists between nicotinic acetylcholine receptors along the post synaptic cleft/motor end plate and acetylcholine.
• Explain the calcium ion flow into and out of the sarcoplasmic reticulum.
• Identify the role of calcium in muscle contraction and describe its relationship with myosin and actin.
• Compare and contrast the effects of having too little or too much acetylcholine and acetylcholine esterase in the synaptic cleft.

muscle; sarin; sarcomere; contraction; NMJ; excitation-contraction; myasthenia gravis; neuromuscular junction; sliding-filament theory

Subject Headings

EDUCATIONAL LEVEL

Undergraduate lower division, Undergraduate upper division

TOPICAL AREAS

TYPE/METHODS

Teaching Notes & Answer Key

Teaching notes.

Case teaching notes are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

Teaching notes are intended to help teachers select and adopt a case. They typically include a summary of the case, teaching objectives, information about the intended audience, details about how the case may be taught, and a list of references and resources.

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Answer Keys are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

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Case Studies in Management of Muscle Cramps

Affiliation.

• 1 Toronto General Hospital / University Health Network, Krembil Brain Institute, University of Toronto, 200 Elizabeth Street, 5ES-306, Toronto, Ontario M6S 4E6, Canada. Electronic address: [email protected].
• PMID: 32703476
• DOI: 10.1016/j.ncl.2020.03.011

Muscle cramps, defined as a painful contraction of a muscle or muscle group, are a common symptom most people have experienced throughout their lifespan. In some cases cramps can be frequent, severe, and disabling, thus requiring medical assessment and intervention. Physiologic states such as pregnancy and exercise are associated with excessive muscle cramps, as are numerous medical and neurologic conditions, medications such as diuretics and statins, and peripheral nerve hyperexcitability syndromes. Treatment options for muscle cramps are limited, although recent studies have shown that mexiletine could be a safe and efficient alternative for patients with amyotrophic lateral sclerosis.

Keywords: Charley horse; Contraction; Hyperexcitability; Muscle cramps; Spasms.

Copyright © 2020 Elsevier Inc. All rights reserved.

Publication types

• Case Reports
• Research Support, Non-U.S. Gov't
• Disease Management*
• Mexiletine / therapeutic use
• Middle Aged
• Muscle Cramp / diagnosis*
• Muscle Cramp / physiopathology
• Muscle Cramp / therapy*
• Voltage-Gated Sodium Channel Blockers / therapeutic use
• Young Adult
• Voltage-Gated Sodium Channel Blockers

• Study protocol
• Open access
• Published: 11 April 2024

Vitamin D as an intervention for improving quadriceps muscle strength in patients after anterior cruciate ligament reconstruction: study protocol for a randomized double-blinded, placebo-controlled clinical trial

• Michael Tim-yun Ong   ORCID: orcid.org/0000-0002-4460-9286 1   na1 ,
• Xiaomin Lu 1   na1 ,
• Ben Chi-yin Choi 1 ,
• Siu-Wai Wan 2 ,
• Qianwen Wang 1 ,
• Gene Chi-wai Man 1 ,
• Pauline Po-yee Lui 1 ,
• Daniel Tik-Pui Fong 1 ,
• Daniel Kam-wah Mok 2 &
• Patrick Shu-hang Yung 1  

Trials volume  25 , Article number:  251 ( 2024 ) Cite this article

96 Accesses

Metrics details

The goal of anterior cruciate ligament reconstruction (ACLR) is to restore the preinjury level of knee function to return to play (RTP). However, even after completing the rehabilitation programme, some patients may have persistent quadriceps muscle weakness affecting knee function which ultimately leads to a failure in returning to play. Vitamin D has been long recognized for its musculoskeletal effects. Vitamin D deficiency may impair muscle strength recovery after ACLR. Correcting vitamin D levels may improve muscle strength.

This is a double-blinded, randomized controlled trial to investigate the effects of vitamin D supplementation during the post-operative period on quadriceps muscle strength in anterior cruciate ligament (ACL)-injured patients. Patients aged 18–50 with serum vitamin D < 20 ng/ml, unilateral ACL injury, > 90% deficit in total quadriceps muscle volume on the involved leg compared with uninvolved leg, Tegner score 7 + , and no previous knee injury/surgery will be recruited. To assess patient improvement, we will perform isokinetic and isometric muscle assessments, ultrasound imaging for quadriceps thickness, self-reported outcomes, KT-1000 for knee laxity, biomechanical analysis, and Xtreme CT for bone mineral density. To investigate the effect of vitamin D status on quadriceps strength, blood serum samples will be taken before and after intervention.

Patients with low vitamin D levels had greater quadriceps fibre cross-sectional area loss and impaired muscle strength recovery after ACL. The proposed study will provide scientific support for using vitamin D supplementation to improve quadriceps strength recovery after ACLR.

Trial registration

ClinicalTrials.gov NCT05174611. Registered on 28 November 2021.

Peer Review reports

Administrative information

Note: The numbers in curly brackets in this protocol refer to the SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defning-standard-protocol-items-for-clinical-trials/ ).

Background and rationale {6a}

In Hong Kong, more than 3000 anterior cruciate ligament reconstructions (ACLR) are carried out annually to restore knee function after an ACL injury. The primary aim of ACLR, particularly for athletes, is to return to sports and recondition the athlete to their pre-injury level of sport. Despite successful surgery and a rigorous rehabilitation process, some athletes still fail to meet the return-to-play (RTP) criteria. Additionally, 23% of those who returned to high-risk sports suffered a second ACL injury [ 21 ].

After ACLR, the patient would undergo post-operative rehabilitation to strengthen the knee muscles. Most of the patients would be expected to RTP by 12 months. Despite a comprehensive rehabilitation programme, a systematic review showed that up to 35% of patients would fail to return to their preinjury level of sport [ 1 ].

Patients can experience substantial quadriceps muscle weakness after ACLR which can persist for over 1 year after surgery. Quadriceps muscle weakness after ACLR is a major limiting factor for functional recovery. It is contributed by arthrogenic muscle inhibition and muscle atrophy, which result from muscle disuse, joint swelling, pain, inflammation, and damage of neuroreceptors in the joint after the surgery. Muscle size is a determinant of muscle strength. Post-operative quadriceps muscle atrophy is inevitable, but muscle strength should be regained through rehabilitation. As the patient continues to exercise during rehabilitation, the atrophic response subsides and the strengthening training stimulates significant hypertrophy in the quadriceps muscle, thus increasing the quadriceps strength [ 6 ]. However, in some patients, this hypertrophic response is insufficient and can lead to persistent quadriceps muscle atrophy after ACLR.

In recent years, there has been a surge of interest in the research field investigating vitamin D status in athletes and examining its musculoskeletal effects. Vitamin D can be obtained from UV-B rays in sunlight or diet. There are 2 major compounds in vitamin D, which are vitamin D2 and vitamin D3. 25-Hydroxyvitamin D3, the active form of vitamin D3, can increase protein synthesis and the number of type II muscle cells by binding to Vitamin D receptors [ 12 ], which in turn leads to improved muscle strength and contraction velocity. Vitamin D deficiency can cause a reduction in type II muscle fibres, negatively affecting muscle function and leading to proximal muscle weakness.

In 2011, a study was conducted to examine the relationship between serum vitamin D levels and the isometric knee extension test in patients with ACL injury [ 3 ]. The study observed patients at the pre-op stage and 3 months after ACLR. The results showed that patients with sufficient levels of vitamin D had significant improvement in the injured side at the post-op stage as compared to their pre-op stage. However, no significant improvement was found in patients with vitamin D insufficiency. Additionally, patients with vitamin D sufficiency had a significantly greater percentage of changes in isometric peak torque as compared to those with insufficiency. This study suggests that patients with vitamin D insufficiency may have impaired muscle strength recovery following their ACLR.

This study would benefit patients who suffered from persistent quadriceps weakness and atrophy after ACLR, thus improving the post-operative outcome. This study aims to conduct a double-blinded, randomized controlled trial to examine the therapeutic effects of vitamin D supplements on improving quadriceps muscle strength in patients with quadriceps muscle weakness after ACL reconstruction. The investigators hypothesize that vitamin D supplements will improve the quadriceps muscle weakness and size of patients with vitamin D deficiency after ACLR.

Objectives {7}

This study aims to conduct a double-blinded, randomized controlled trial to examine the therapeutic effects of vitamin D supplements on improving quadriceps muscle strength in patients with quadriceps muscle weakness after ACLR.

Trial design {8}

This study is a randomized, double-blinded, placebo-controlled clinical trial to investigate the effects of vitamin D supplements for patients with quadriceps muscle weakness after ACLR. The intervention group receives 2000 IU vitamin D 3 per day for 16 weeks whereas the control group receives a placebo.

Data is assessed at the four measurement time points from the participants:

Baseline/inclusion

First follow-up: 8 weeks after intervention commencement

Second follow-up: 16 weeks after intervention commencement

Third follow-up: post-intervention at 2 months

Methods: participants, interventions, and outcomes

Study setting {9}.

Patients are recruited from a local hospital in Hong Kong. These patients will be followed up at the Orthopaedics Outpatient Clinic at the Prince of Wales Hospital for clinical examination and questionnaire filling. While for the muscle assessments, it will be conducted at the Sports Medicine and Rehabilitation Centre at the Chinese University of Hong Kong Medical Centre.

Eligibility criteria {10}

The inclusion criteria are as follows:

Aged 18–50 with unilateral ACL injury

Sporting injury with a Tegner score of 7 + 

Serum D level remained < 20 ng/ml

Limb symmetry index of isokinetic quadriceps strength < 90% in the injured leg of the contralateral leg

Both knees without a history of injury/prior surgery

The exclusion criteria are as follows:

Concomitant bone fracture, major meniscus injury, or full-thickness chondral injuries requiring altered rehabilitation programme post-operatively

Pre-operative radiographic signs of arthritis

Metal implants that would cause interference on MRI

Non-HS graft for ACLR

Patient non-compliant with the rehabilitation programme

Regular sunbed users

Who will take informed consent? {26a}

Trained research assistants will obtain written informed consent from all participants prior to their participation in this study. Our research assistants will first explain to eligible participants our programme in detail. The study will be carried out in compliance with the Declaration of Helsinki and the ICH-GCP. Ethical approval will be obtained from the local IRB before the study starts. Informed consent must be obtained from all patients in order to participate in the study.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Consent of participant data and biological specimens are also included in the informed consent. Blood specimens in this study will be disposed of after testing and will not be used for genetic analysis or used in other studies. Every participant will be represented by an ID number, and personal information such as name, address, and telephone number will be kept confidential before, during, and after the study.

Interventions

Explanation for the choice of comparators {6b}.

Patients randomized to the control arm will receive a placebo with the same appearance as vitamin D 3 . As a placebo will look and taste like vitamin D 3 , this can ensure the participants are blinded to the treatment. The utilization of a placebo that closely mimics the appearance and flavour of vitamin D3 will effectively blind the participants to their treatment.

Intervention description {11a}

For the proposed study, we will use 2000 IU/day as advised by the Endocrine Society [ 10 ]. A previous study has shown that 2000 IU/day for 4 months showed significant improvement in muscle strength [ 22 ]. Therefore, for the proposed study, we will use 2000 IU/day for a duration of 16 weeks. Subjects will be randomized into two study groups: (1) placebo group—patients receive placebo; (2) intervention group—patients receive a daily dose of 2000 IU of vitamin D3 supplements. Supplements will be dispensed to participants in baseline and 1st follow-up to increase the subject compliance.

All study tablets including the supplement and placebo will be manufactured according to the Good Manufacturing Practice (GMP) guidelines for quality assurance. They will be taken with water at breakfast, one tablet at a time and once daily. The treatment will last for 16 weeks after which the supplementation will be stopped. Subjects will continue with their usual lifestyles in diet and physical activity without receiving any other treatment for muscle health.

Criteria for discontinuing or modifying allocated interventions {11b}

Vitamin D has been considered safe for users when taken in appropriate doses [ 13 ]. Participants will be advised that in the event of nausea, vomiting, muscle weakness, or confusion, they should discontinue taking supplements and seek medical attention. The medical staff will perform the evaluation determining if immediate removal from the study is necessary for their best interest to safeguard their health.

Strategies to improve adherence to interventions {11c}

Patients will be contacted weekly for their intake of the intervention and 1 week before the assessment to enhance the attendance rate. Special assessment session on the weekend or in the evening will be arranged under special circumstances to enhance subject compliance. Patients who default a scheduled appointment will be contacted by the investigators to re-arrange another appointment within 1 week. In the case of patient non-compliance, study personnel would remove the patient from the study only when multiple failed attempts to contact and convince the patient occur. If the patient chooses to withdraw from the study before the end of the study period, the reason and termination date will be recorded. As far as possible, we will invite patients who would like to withdraw to attend the final assessment.

Relevant concomitant care permitted or prohibited during the trial {11d}

Participants remain on their standard treatment and medication procedures throughout the study period, and clinicians are advised to manage participants in the usual manner subject to the caveats outlined above.

Provisions for post‑trial care {30}

Not applicable, since ancillary and post-trial care is provided within the standard care.

The primary objectives of this study are to track the changes in peak torque and fatigue index (FI) of isokinetic muscle strength over a period of 6 months. The peak torque, measured in Newton metre (Nm), will be the highest recorded value among the 30 repetitions during the isokinetic muscle strength test, and the FI will be utilized to determine the per cent decrease for each variable that correlates with muscle endurance. Secondary outcome measures include (1) assessment of isometric muscle strength through quadriceps rate of torque development (RTD) and central activation ratio (CAR), (2) quadriceps muscle volume and muscle thickness, (3) evaluation of serum 25(OH)D using LC-Qtrap/MS, (4) measurement of passive knee laxity using KT-1000 knee ligament arthrometer (MEDmetric Corp., San Diego, CA, USA), (5) analysis on the reaming size of the bone using XtremeCt II, (6) the evaluation of ground reaction force will be carried out using a synchronized force plate located at the centre of the capture volume at 1000 Hz, (7) assessment of knee joint moments will be assessed by the skin marker-based motion analysis system, (8) distance by single-leg hop test, and (9) self-reported outcome assessing pain, disability, and activity level on knee function will be evaluated during the 6 months of follow-up.

Participant timeline {13}

The SPIRIT reporting guidelines were used to ensure the completion of the study protocol (Additional file 1 ) [ 4 ]. The study flowchart is illustrated in Fig.  1 .

Study flowchart

Sample size {14}

Quadriceps muscle strength will be employed as the primary outcome for sample size estimation. As reported [ 22 ], the difference in quadriceps between the two groups is 0.88. It is estimated that a sample size of 28 in each group will have 90% power to detect a significant difference using a two-sided independent t test with a 0.05 significance level (G*Power 3.1.9.4). Taking account of the 20% dropout rate, we further increase the sample size to n  = 30 for each arm (total n  = 60).

Recruitment {15}

Patients who have persisting quadriceps muscle weakness after ACLR will be recruited consecutively.

The centre staff will assist in identifying eligible patients from the Department of Orthopaedics and Traumatology at Prince of Wales Hospital, Hong Kong, based on the inclusion and exclusion criteria and send them to us for screening. These patients will be screened at the Sports Medicine and Rehabilitation Centre at the Chinese University of Hong Kong Medical Centre. The patients will be explained the study procedures by the principal investigator. Patients who consent to participate in the study will attend a scheduled visit for baseline examination. The completion of the trial is expected to take 36 months.

Assignment of interventions: allocation

Sequence generation {16a}, randomization and blinding.

A total of 60 patients will be enrolled. Participants will be randomized into 1:1 allocation, blocked randomization with 30 participants in the vitamin D group and 30 participants in the placebo group. The randomization will be done using a computer randomization program before the intervention. This will be overseen by a biostatistician who is not involved in the recruitment of patients and data analysis. Hence, both participants and the research personnel are blinded until the completion of treatment.

Concealment mechanism {16b}

Allocation concealment will be ensured as the computer randomization programme will not release the randomization code until the patient has been recruited into the trial. Vitamin D and placebo will be dispensed to participants in visually indistinguishable forms by Clinical Research Pharmacy based on the randomization code. Hence, patients and investigators are fully blinded until the completion of treatment. Outcome assessors and statisticians are also blinded.

Implementation {16c}

The principal investigator will enrol participants. The computer randomization program will generate the allocation sequence at a 1:1 ratio. An independent research staff will assign participants to interventions.

Assignment of interventions: blinding

Who will be blinded {17a}.

Participants are blinded to the intervention. The research assistant who assists in consent seeking and monitoring of progress and adverse events will not be involved in outcome assessment. The assessor who will be another trained research assistant will be blinded to the randomization status and will not be involved in the intervention. The statistician responsible for the randomization is not involved in other parts of the study including data analysis.

Procedure for unblinding if needed {17b}

In normal circumstances, the blinding will be maintained unless a serious adverse event occurs. Unblinded participants will then exit the trial, and the medical conditions will be managed accordingly. The management results will be recorded on the clinical report form and reported to the Joint Clinical Research Ethics Committee of the Chinese University of Hong Kong and the New Territories East Cluster of the Hospital Authority.

Data collection and management

Plans for assessment and collection of outcomes {18a}, anthropometric measurement.

Body mass index (BMI) would be calculated by the measured height and weight. We would measure the waist circumference as well. Subcutaneous fat would be measured using skinfold techniques for the triceps brachii and biceps brachii.

Biochemical assays

Blood samples will be taken under non-fasting conditions. The serum obtained (5 ml) will be immediately stored at − 80 °C until analysis. Quantitative analysis for serum 25(OH) Vit-D assay will be performed using LC-Qtrap/MS.

Isokinetic muscle strength assessment

The dynamometer (Biodex System 4, Biodex Medical Systems Inc., New York, USA) will be used. Prior to the test, the subjects will engage in a standardized warm-up exercise consisting of 5 min of cycling. The knee extension and flexion will be tested in concentric and concentric contractions at 60°/s and 180°/s [ 2 ]. Subjects will be seated on the dynamometer chair with their hips flexed to 85°. The speed of 180°/s is chosen to perform the fatigue test since high-speed workouts are expected to tire the fast-twitch muscle fibres more quickly [ 17 ]. For calculating peak torque, the single highest value within the 30 repetitions will be considered. The fatigue test will reflect muscle endurance, and the trends for peak torque, work, and power will be analysed. To calculate the percentage decrease for each variable, the FI (fatigue index) will be used [ 14 ]. The formula for percentage decrease is 100 − [(last 5 repetitions/first 5 repetitions) × 100]. If an individual fails to achieve their peak torque within the first 3 repetitions, a second F.T. will be calculated using the formula: Per cent decrease = [100 − [(last 5 repetitions/highest consecutive 5 repetitions) × 100]. The highest consecutive five repetitions will be determined by values attained from the repetitions immediately before and following the single highest repetition value [ 14 ]. The re-test reliability has been proven [ 18 ].

Isometric muscle strength assessment

After warming up on a stationary bicycle for 5 min, the strength of the quadriceps muscle will be measured using a Biodex dynamometer (Biodex System 4, Biodex Medical Systems Inc., New York, USA) through maximal voluntary isometric contractions (MVIC). The uninjured limb will be tested first, followed by the injured limb. To isolate knee movement, the participants will be stabilized with straps placed over the trunk, pelvis, and thigh, with the hip flexed at 90° and the knee flexed at 45°, respectively [ 11 ]. To get the participants accustomed and warmed up, three sub-maximal voluntary contractions will be performed. Afterward, the participants will be instructed to perform three 5-s MVICs, with a 30-s rest period between each contraction. During the contractions, participants will be motivated to “kick as fast and hard as possible” verbally. The highest peak torque achieved among the three contractions will be collected as the MVIC and normalized by body mass for analysis.

The quadriceps rate of torque development (RTD) will be obtained from the MVIC test. The early and late RTD values will be calculated by determining the average slope of torque versus time curve measured from 0 to 50 ms (RTD0-50) and 100 to 200 ms (RTD100-200), respectively, after the onset of MVIC [ 8 ]. The onset of a contraction is identified as the torque ≥ 20 Nm. The highest RTD will be selected and normalized to body mass for analysis.

The superimposed burst technique (SIB) will be used to measure activation failure. This technique delivers a series of electrical stimulations to the quadriceps during a MVIC, causing a transient increase in muscle torque. All participants will be given a minimum of 5 min of rest after completing the MVIC test to prevent muscle fatigue. The position of SIB is the same as the MVIC test on the Biodex dynamometer. Two self-adhesive electrodes [ValuTrode (7.5 × 13 cm), Axelgaard manufacturing, CA, USA] will be attached to the quadriceps along the femoral nerve. All participants will be instructed to perform three additional 5-s quadriceps MVICs. A 1-min rest interval is provided between each contraction. During the MVIC of the quadriceps, an electrical stimulator (DS7R; Digitimer, Welwyn Garden City, UK) controlled by the Signal 7.05a software (CED Software, Cambridge, UK) will automatically deliver a supramaximal electrical stimulus. The stimulus consisted of 10 pulses with a pulse duration of 600 μs, delivered at a rate of 100 pulses per second. This occurred at the 3rd second of the MVIC. The intensity of the supramaximal electrical stimulus is determined prior to the SIB test. Electrical stimulations will be progressively delivered to the quadriceps, increasing by 100 mA each time until the stimulation-induced torque reached a plateau at rest. To ensure full stimulation of the quadriceps, the SIB test utilizes a current intensity of 120% plateau. In order to ensure maximal participant exertion, a successful trial is defined as achieving greater than 90% MVIC of quadriceps torque prior to the electrical stimulation. To represent full activation of the quadriceps, a central activation ratio (CAR) will be utilized. The following formula is used to calculate CAR: CAR = MVIC/(MVIC + stimulation provoked torque (SPT)). For analysis, the highest CAR obtained from three successful trials was recorded.

Radiological assessment

Ultrasound imaging: The muscle thickness of the vastus medialis (VM), vastus lateralis (VL), and rectus femoris (RF) on both the injured and uninjured leg will be measured using the Aixplorer® ultrasound system (SuperSonic Imagine, Aix-en-Provence, France) and a linear transducer probe with a bandwidth of 2–10 MHz (SuperLinear™ SL10-2, Vermon, Tours, France). The participants will lie on a treatment table in a supine position during the assessment. A measuring tape will be used to locate VM, VL, RF, and the patella by palpation, and then marked with a pen for reference. Following the guidelines below, we consistently measure and label the locations as the three muscle groups for ease of comparison across patients. The following are the locations of specific points on the leg: RF is located at half of the distance from the anterior superior iliac spine (ASIS) to the superior pole of the patella, VM is located at one-fifth of the distance away from the midpoint of the medial patella border to the ASIS, and VL is located at one-third of the distance from the midpoint of the lateral patella border to the ASIS. After locating the anatomical points, excess contact gel will be applied to these points. The transducer probe will be aligned in the transverse plane and moved along the entire muscle bundle to capture a view of the VM, VL and RF. The operator will position the probe into the sagittal plane to measure muscle thickness upon the marked anatomical points. Minimal pressure will be applied to the limb to prevent muscle deformation. The results will be derived from three measurements averaged.

HR-pQCT: The HR-pQCT (ExtremCT II, Scanco, Switzerland) will be used to measure the size of the bone shell at the graft tunnel interface in the injured knees. The scan will consist of a total of 1344 axial slices with an image matrix of 2304 × 2304, taken at a nominal isotropic voxel size of 60.7 μm. The scan region will be defined by the scout view image that is acquired in the sagittal plane. The total scanning length will be 81.6 mm, covering the tunnel from the proximal tibia to the distal femoral condyle. The X-ray settings used will be 68 kVp, 1470 μA, 100 ms integration time, and 156 mAs per stack (168 slices). To avoid artefacts, patients will be instructed to sit still during the measurement. The image segmentation will be performed to select the bone shell features at graft tunnel interfaces near the femoral and tibial intra-articular apertures. This will be done using standardized threshold values at a thickness of approximately 2.5 mm (40 slices). The geometric transformation will be used to adjust for variations in the angle between the scanning axis and the tunnel axis by using a cosine function. The bone shell size will be presented as a summation of the segmented angle of incidence (AOI) of 40 slices to yield a volume of interest (VOI) in μm 3 .

Passive knee laxity

To measure the anterior–posterior knee laxity, the KT-1000 knee ligament arthrometer (MEDmetric Corp, San Diego, CA, USA) will be used. A manual force test will be applied until a 30-lb sound signal is activated. Three trials will be performed.

Biomechanics-motion analysis

The lower-body marker set-up will be used to assess kinematics via a skin marker-based motion analysis system (Vicon MX, Oxford, UK) following the OSTRC standard protocol, utilizing 16 cameras and 16 reflective skin markers. The kinetic variables including vertical and horizontal ground reaction force (GRF) and joint moments will be measured using a synchronized force plate (0.60 × 0.40 m, model OR6-7, AMTI, Watertown, MA) at the centre of the capture volume at 1000 Hz.

Single-leg hop (SLH) task: The SLH test will be performed as reported in the previous studies [ 19 ]. Three trials will be performed on each leg followed by familiarization. The SLH test will be considered valid if the patients can hop the maximum distance while keeping their balance for at least 2 s after landing.

Single leg squat (SLS) task: The subjects will begin by standing upright with their toes pointed forward and then squat down at their own pace. Once they reach the designated flexion angle, they will be asked to hold the position for ten seconds. If the subject is unable to maintain their balance, the trial will be deemed invalid. All participants will practice enough to achieve the required knee angle, which is between 40 and 50 degrees.

Self-reported outcomes

Lysholm Score: Lysholm Knee Score is a questionnaire that examines knee-specific symptoms and function of daily living. It consists of eight items, with a total score ranging from 0 to 100 and a higher score indicates a better outcome with fewer symptoms of disability.

International Knee Documentation Committee Subjective Knee Form (IKDC): IKDC is a self-reported questionnaire that measures symptoms, knee function and activity of daily living. The questionnaire consists of 10 questions, with a total score ranging from 0 to 100 and a higher score indicates greater knee function.

Tegner Score: The Tegner Activity Scale will be used to assess activity levels related to sports on a scale of 0 to 10. Zero represents a low activity level, and 10 represents the highest activity level.

Physical Activity Questionnaire: The level of physical activities during the past year will be evaluated with a validated Chinese version of the quantitative physical activity questionnaire adapted from Baecke et al. [ 9 ].

Food Frequency Questionnaire: The level of estimated vitamin D level taken from food will be evaluated with a validated Chinese version of the food frequency questionnaire.

Sunlight Exposure Questionnaire: The level of estimated vitamin D level absorbed from sunlight exposure will be evaluated with a validated Chinese version of the sunlight exposure questionnaire.

The assessment schedule is shown in Table  1 .

Plans to promote participant retention and complete follow-up {18b}

Patients will be contacted weekly for their intake of the intervention and 1 week before the assessment to enhance the attendance rate. Special assessment session on the weekend or in the evening will be arranged under special circumstances to enhance subject compliance. Patients who default a scheduled appointment will be contacted by the investigators to re-arrange another appointment within 1 week.

Data management {19}

Clinical data will be collected and recorded by trained research assistants in our research centre. Clinical examination data will be entered on case report forms and then entered electronically. Consistency checks by another technician will be performed to ensure data entry accuracy. All data will be stored in password-protected computers. The study will be conducted in compliance with Good Clinical Practices to ensure the rights and well-being of the participants and that the data collected are complete and verifiable from source documents. Patients are free to withdraw from the study at any time without giving any reasons, and their medical care or legal rights will not be affected. Patient files will be maintained in storage for a period of 3 years after completion of the study.

Confidentiality {27}

All personal information and consents on enrolled patients collected on paper versions will be kept in locked units at the participating practice and later at the coordinating centre to be archived. Each patient will be assigned an identification code. All information collected and inputted on the electronic database will be based on the identification code and therefore does not contain any personalized information that enables the identification of the patient. The document containing the information on the identification code and the identity of the patient will be kept separate from the study data files and data sheets. The patient identification code list and database can only be retrieved by dedicated study team members or be inspected by study monitors for quality checking and verification.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

Blood will be collected at the clinical sites for evaluation. After arrival at the local research laboratory at each site, the samples will be collected, transported, stored, and prepared according to local protocols. Blood will be stored at 2–8 °C before handling within the required time. All samples collected during the trial will be labelled with the patients’ identification code and will not contain any identifiable data. Patients have the option of consenting to their samples being stored for future research uses. Samples will be stored anonymously at a central location for a minimum of 5 years and a maximum of 10 years after completion of the study, after which these specimens will be destroyed by incineration according to local guidelines and protocols. The potential usage of the stored samples is included in the informed consent form. Nevertheless, further usage of the samples will need to be approved by the institutional ethical committee.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}.

Statistical analysis will be performed using the SPSS software (SPSS 26.0). The normality of the data will be tested using the Kolmogorov–Smirnov test. A repeated-measures one-way analysis of variance (ANOVA) will be used to compare quadriceps muscle strength (isokinetic assessment), serum myokine levels, and results of questionnaires at the time points. A non-parametric Mann–Whitney U test will be used to compare questionnaire results (ordinal data) between the intervention and placebo groups.

Interim analyses {21b}

Interim analysis will be performed when approximately 10% of our sample have completed follow-up assessments. The preliminary findings will be presented in conference to promote our study.

Methods for additional analyses (e.g. subgroup analyses) {20b}

Additional analyses will include subgroup analyses to estimate treatment effects for both female and male participants.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

We will generally perform the analysis using the intention-to-treat (ITT) at the subject level for each outcome. All the participants with a recorded outcome will be included in the analysis according to the intervention group to which they have been randomized. Additionally, we will take the cluster-randomized crossover design effect into consideration. Adjustment for multiple comparisons among interventions will be used. To assess the risk of bias related to orthopaedic wards that have not completed patient recruitment, multiple imputations will be performed for the primary outcome and presented as sensitivity analyses. At the subject level, when a variable is missing, we will assume that most likely the missing variable has a normal or mean value.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

The protocol has been uploaded on ClinicalTrials.gov (ID: NCT05174611). The data of this study will also be available from the principal investigator upon reasonable request.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}.

The principal investigator is responsible for the design of the study and the coordination of different cooperation partners. The research team comprises the trial steering committee responsible for the recruitment, assessments, output delivery, and data analysis. The patients after cruciate ligament reconstruction who fulfil the inclusion criteria will be invited to join the study. However, there will be no public involvement.

Composition of the data monitoring committee, its role, and reporting structure {21a}

The principal investigator and co-investigators will monitor the data collection and storage to ensure that the data is kept and used in accordance with the protocol. A statistician, who is independent from the sponsor and any competing interests, will be responsible to inspect clinical data collected during the study period, review the interim analysis, and report back to the investigators for any action required. The data monitoring committee is not considered as PEMF is a low-risk intervention.

Adverse event reporting and harms {22}

Although vitamin D is presumed safe, adverse events will be checked by the investigators at every follow-up visit. Any adverse event, whether they are related to the study or not, will be recorded in the adverse effect report form provided by the Hong Kong Hospital Authority using standard adverse event language. A serious adverse event will be reported to the Hong Kong Hospital Authority Research Ethics Committee within 24 h of the event. The principal investigator will be responsible to follow the management of the serious adverse event until resolution or conclusion. The investigators and the trial steering committee will determine whether an adverse event or serious adverse event is related to the study intervention. The intervention will be stopped immediately if the reported event is related, with a referral to seek medical attention provided by the principal investigator.

Frequency and plans for auditing trial conduct {23}

As per the university’s requirement, an independent auditor will conduct the annual review throughout the project period.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

There is no plan for modifying the protocol at this juncture. However, any amendment to the protocol will be submitted by the principal investigator to be approved by the research grant committee of the Direct Grant and the ethical committee before implementation. In addition, the trial participants will also be notified as well.

Dissemination plans {31a}

The research findings will be published in peer-reviewed journals and disseminated to healthcare professionals, the public, and other relevant groups as soon as the results are available. The funder has no role or restriction in the decision of publication.

The primary goals of ACLR are to restore knee function in patients who have suffered from ACL injury and enable them to RTP. However, patients commonly experience persistent weakness in their quadriceps muscle after undergoing ACLR, and a significant percentage of them (35%) are unable to achieve RTP [ 8 ]. The weakness of the quadriceps muscles can negatively affect athletic performance and increase the risk of re-injury. Vitamin D has long been recognized for its musculoskeletal effects. Patients with low vitamin D levels had greater quadriceps fibre cross-sectional area loss after ACLR compared to those with normal or higher vitamin D levels [ 20 ]. Our study proposes using vitamin D to promote muscle gains in patients experiencing persisting muscle weakness after ACLR.

Our study may bring various benefits to patients after ACLR. After an ACL injury, patients experience a decline in neuromuscular function, which lasts even after the operation [ 15 ]. Vitamin D has been shown to play a role in improving neuromuscular function. Vitamin D supplementation may lead to improved neuromuscular function in older adults, potentially aiding in the prevention of falls [ 7 , 16 ]. The presence of vitamin D receptors in the skeletal muscle tissue and their role in muscle strength and coordination further support the link between vitamin D and neuromuscular function [ 5 ]. Therefore, correcting vitamin D status may have potential benefits for enhancing neuromuscular function in individuals, including patients after ACLR.

Our study design has strengths. Firstly, the format of Clinical Research Pharmacy as randomized clusters will enhance the fidelity of the interventions. Second, dispensing supplements in two installments will enhance the subject compliance and prevent a high drop-out rate. Thirdly, two questionnaires will be used to estimate daily vitamin D intake and eliminate its effect. However, there is a limitation to this study design. Patient recruitment with inconsistent post-operative time intervals may result in biased outcomes.

Trial status

The protocol version 1 was dated 08 December 2022, and version 7 was dated 06 March 2023. Reasons for revision are described in {3}.

Study recruitment started on 15 March 2023, and the recruitment is still ongoing. The recruitment will finish on 1 March 2025, and the completion of the trial remains scheduled on 1 September 2025.

Availability of data and materials {29}

Any data required to support the protocol can be supplied on request.

Abbreviations

Anterior cruciate ligament reconstruction

Return to play

Anterior cruciate ligament

Good Manufacturing Practice

Fatigue index

Rate of torque development

Central activation ratio

Body mass index

Maximal voluntary isometric contractions

Superimposed burst technique

Stimulation provoked

Vastus medialis

Vastus lateralis

Rectus femoris

Anterior superior iliac spine

Segmented angle of incidence

Volume of interest

Ground reaction force

Single-leg hop

Single-leg squat

International Knee Documentation Committee Subjective Knee Form

Intention-to-treat

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Acknowledgements

Not applicable.

Fully funded by the Direct Grant for Research, The Chinese University of Hong Kong (Ref: 2021.037). The funder has no role in the design of the study; collection, analysis, and interpretation of the data; and writing of the manuscript.

Author information

Michael Tim-yun Ong and Xiaomin Lu contributed equally to this work.

Authors and Affiliations

Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Room 74029, 5/F, Lui Che Woo Clinical Science Building, Prince of Wales Hospital, Shatin, Hong Kong SAR, China

Michael Tim-yun Ong, Xiaomin Lu, Ben Chi-yin Choi, Qianwen Wang, Gene Chi-wai Man, Pauline Po-yee Lui, Daniel Tik-Pui Fong & Patrick Shu-hang Yung

Department of Food Science and Nutrition, The Hong Kong Polytechnic University, TU314, Block U, Hung Hom, Hong Kong SAR, China

Siu-Wai Wan & Daniel Kam-wah Mok

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MTYO received the funding. The research question was formulated by MTYO and PSHY, and the study design was jointly developed by MTYO, GCWM, and PSHY. The study was conducted by MTYO, XML, GCWM, BCYC, QW, DKWM, PPYL, DTPF, and PSHY. The manuscript was written by MTYO and XML, and it has been approved by all the authors before submission. This manuscript is not written by professional writers.

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Correspondence to Michael Tim-yun Ong or Daniel Kam-wah Mok .

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Ethics approval and consent to participate {24}.

This study was reviewed and approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Reference number: 2020.623-T). Written informed consent will be obtained from all individual participants included in the study.

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Not applicable, as no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. Informed consent materials are attached as supplementary materials.

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The authors declare that they have no competing interests.

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Ong, M.Ty., Lu, X., Choi, B.Cy. et al. Vitamin D as an intervention for improving quadriceps muscle strength in patients after anterior cruciate ligament reconstruction: study protocol for a randomized double-blinded, placebo-controlled clinical trial. Trials 25 , 251 (2024). https://doi.org/10.1186/s13063-024-08094-w

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Received : 10 January 2024

Accepted : 03 April 2024

Published : 11 April 2024

DOI : https://doi.org/10.1186/s13063-024-08094-w

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• Quadriceps strength
• Anterior cruciate ligament (ACL)
• Anterior cruciate ligament reconstructions (ACLR)

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Inherited predisposition for higher muscle strength may protect against common morbidities

A study conducted at the Faculty of Sport and Health Sciences at the University of Jyväskylä showed that a genetic predisposition for higher muscle strength predicts a longer lifespan and a lower risk for developing common diseases. This is the most comprehensive international study to date on hereditary muscle strength and its relationship to morbidity. The genome and health data of more than 340,000 Finns was used in the research.

Muscle strength, especially hand grip strength, can indicate an individual's physiological resources to protect against age-related diseases and disabilities, as well as their ability to cope with them. Age-related loss of muscle strength is individual and influenced not only by lifestyle but also by genetics.

The study revealed that individuals with a genetic predisposition for higher muscle strength have a slightly lower risk for common noncommunicable diseases and premature mortality. However, it did not predict better survival after acute adverse health events compared to the time before illness onset.

"It seems that a genetic predisposition for higher muscle strength reflects more on an individual's intrinsic ability to resist and protect oneself against pathological changes that occur during aging than the ability to recover or completely bounce back after severe adversity," says doctoral researcher Päivi Herranen from the Faculty of Sport and Health Sciences.

The research utilized a unique study population

Muscle strength is a multifactorial trait influenced by lifestyle and environmental factors but also by numerous genetic variants, each with a very small effect on muscle strength. In this study, the genetic predisposition for muscle strength was defined by constructing a polygenic score for muscle strength, which summarizes the effects of hundreds of thousands of genetic variants into a single score. The polygenic score makes it possible to compare participants with an exceptionally high or low genetic predisposition for muscle strength, and to investigate associations with inherited muscle strength and other phenotypes, in this case, common diseases.

"In this study, we were able to utilize both genetic information and health outcomes from over 340,000 Finnish men and women," Herranen explains.

"To our knowledge, this is the first study to investigate the association between a genetic predisposition for muscle strength and various diseases on this scale."

Further research on the effects of lifestyles is still needed

Information about the genetic predisposition for muscle strength could be used alongside traditional risk assessment in identifying individuals who are at particularly high risk of common diseases and health adversities. However, further research on the topic is still needed.

"Based on these results, we cannot say how lifestyle factors, such as physical activity, modify an individual's intrinsic ability to resist diseases and whether their impact on health differs among individuals due to genetics," Herranen notes.

The study utilized the internationally unique FinnGen dataset, compiled through the collaboration of Finnish biobanks. The dataset consisted of 342,443 Finns who had given their consent and provided a biobank sample. The participants were aged 40 to 108 years, and 53% of them were women. The diagnoses selected for the study were based on the leading causes of death and the most significant noncommunicable diseases in Finland. Selected diagnoses included the most common cardiometabolic and pulmonary diseases, musculoskeletal and connective tissue diseases, falls and fractures, mental health and cognitive disorders, cancers, as well as overall mortality and mortality from cardiovascular diseases.

The study is the second publication of Päivi Herranen's doctoral thesis, which investigates how genetics and environmental factors affect biological aging, particularly the weakening of muscle strength and functional capacity with age. The research is part of the GenActive project, funded by the Research Council of Finland and the Juho Vainio and Päivikki and Sakari Sohlberg foundations. The project is led by Assistant Professor and Academy Research Fellow Elina Sillanpää. The research was conducted in collaboration with the Gerontology Research Center (GEREC), the Institute for Molecular Medicine Finland (FIMM), and the FinnGen research project.

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Materials provided by University of Jyväskylä - Jyväskylän yliopisto . Note: Content may be edited for style and length.

Journal Reference :

• Päivi Herranen, Kaisa Koivunen, Teemu Palviainen, Urho M Kujala, Samuli Ripatti, Jaakko Kaprio, Elina Sillanpää, FinnGen. Genome-Wide Polygenic Score for Muscle Strength Predicts Risk for Common Diseases and Lifespan: A Prospective Cohort Study . The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences , 2024; 79 (4) DOI: 10.1093/gerona/glae064

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Organoids reveal how to protect the brain against dementia and ALS following traumatic injury, according to USC Stem Cell study

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$3.95 million CIRM grant establishes USC ASCEND Center to make stem cell-derived organ models accessible to all

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A traumatic brain injury (TBI) can quadruple your risk for developing dementia, and also increase your chances of developing neurodegenerative diseases such as ALS. In a new study published in Cell Stem Cell , USC scientists use lab-grown human brain structures known as organoids to offer insights into why this is the case and how to mitigate the risk.

In the study, former postdoc Jesse Lai and postdoc Joshua Berlind from the USC Stem Cell laboratory of Justin Ichida used human patient-derived stem cells to grow rudimentary brain structures known as organoids in the lab. They then injured these organoids with high-intensity ultrasound waves.

The injured organoids showed some of the same features seen in TBI patients, including nerve cell death and pathological changes in tau proteins, as well as in a protein called TDP-43.

The scientists found that the pathological changes in TDP-43 were more prevalent in organoids derived from patients with ALS or frontotemporal dementia, making their nerve cells more suspectable to dysfunction and death following injury. This suggests that TBI might increase the risk of developing these diseases even more for patients with a genetic predisposition. The worst injuries were sustained by nerve cells that share information—called excitatory neurons—located in the deep layers of the organoids.

In their search for ways to protect these neurons against the effects TBI, the scientists identified a gene called KCNJ2, which contains instructions for making channels that selectively allow potassium to pass through the cell membrane, helping enable muscle contraction and relaxation. Inhibiting this gene had a protective effect on organoids derived from patients with and without ALS, as well as on mice, following a TBI.

“Targeting KCNJ2 may reduce the death of nerve cells after TBI,” said Ichida, who is the John Douglas French Alzheimer’s Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, and a principal investigator at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “This could have potential as either a post-injury treatment or as a prophylactic for athletes and others at high risk for TBI.”

About the authors and the study

Co-corresponding author Ichida is also a co-founder of AcuraStem and Modulo Bio, a Scientific Advisory Board (SAB) member at Spinogenix and Vesalius Therapeutics, and an employee in the Research and Early Development group at BioMarin Pharmaceutical. Co-corresponding author Lai and co-author Violeta Yu were both employees of Amgen during the study, and currently work at Dewpoint Therapeutics. Named companies were not involved in this research project.

First author Berlind is a PhD student in the Ichida Lab. Additional co-authors are Gabriella Fricklas, Cecilia Lie, Jean-Paul Urenda, Kelsey Lam, Naomi Sta Maria, Russell Jacobs, and Zhen Zhao from USC.

Fifty percent of the work was supported by federal funding from the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (grant F31NS117075), NINDS (grant R01 1R01NS097850-01), and the Department of Defense (grant 12907280). The project was also privately funded by an Amgen postdoctoral fellowship, the New York Stem Cell Foundation, the Tau Consortium, the Harrington Discovery Institute, the Alzheimer’s Drug Discovery Foundation, the Association for Frontotemporal Dementia, and the John Douglas French Alzheimer’s Foundation.

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