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

Abstract

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.

Keywords: molecular mechanisms; molecular structure; muscle health and disease; muscle physiology; skeletal muscle.

Figure 1

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

Figure 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

Figure 3

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

Figure 4

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

Figure 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)

Figure 6

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

Figure 7

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 Ca²⁺ cycling and storage within the sarcoplasmic reticulum. Calsequestrin is a high capacity Ca²⁺ 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

Figure 8

(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 Ca²⁺ 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

Figure 9

Cellular events underlying force generation. Force generation begins with arrival of an impulse, which changes the Ca²⁺ dynamics within muscle leading to a highly orchestrated set of specific changes to the molecular structure of the actomyosin complex bringing about sarcomeric contraction

Figure 10

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

Figure 11

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

Figure 12

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

Figure 13

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

Figure 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

Figure 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

Figure 16

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)