Author(s): William A. Ramos-Guasp, MD, Edwardo Ramos, MD
Originally published: January 17, 2024 Last updated: January 17, 2024
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Overview and Description

Introduction

The primary function of skeletal muscle is to generate force and produce movement. This task is achieved by way of specialized cells capable of converting chemical energy into mechanical energy. Mostly under voluntary control, skeletal muscle is essential for everyday activities such as maintaining body posture, mobility, speech and breathing. Accordingly, abnormal function of the musculoskeletal system can lead to life-threatening diseases.

This article will offer a limited overview of the basic physiological principles of skeletal muscle, with particular emphasis on its fundamental ability to generate force and how alterations in both structure and function can lead to disease.

Organization of skeletal muscle

Muscle fibers—or myofibers—are elongated, multinucleated cells which represent the basic contractile unit of skeletal muscle. Each individual myofiber is covered by a layer of connective tissue called the endomysium. A group of myofibers form a fascicle, which is covered by another layer of connective tissue called the perimysium. Finally, a group of fascicles form a muscle, which is covered by a final layer of connective tissue called the epimysium. All three layers of connective tissue join at the ends of each muscle and merge with the tendon, anchoring the muscle to bone.1

Microscopically, each myofiber is covered by a cell membrane—or sarcolemma— which, similar to the membrane of other eukaryotic cells, is composed of a lipid bilayer and an outer coat of polysaccharides that connects to the basement membrane. An important feature of the sarcolemma is that it penetrates the muscle cell by way of plasma membrane invaginations called transverse tubules (T tubules). T tubules are flanked by two projections of the sarcoplasmic reticulum called the terminal cisternae. The sarcoplasmic reticulum is involved in the storage, release, and reuptake of intracellular calcium (Ca2+) in skeletal muscle. One T tubule and its two flanking terminal cisternae form a triad; a structure that facilitates transmission of the action potential into the interior of the cell and, as we will discuss later, is essential for the excitation-contraction coupling mechanism.2

Inside their cytoplasm—or sarcoplasm—muscle fibers contain a dense array of cylindrical organelles called myofibrils. Approximately 1-2mm in diameter, myofibrils account for nearly 80% of the volume a muscle. Each myofibril is in turn composed of repeating units of thick and thin protein filaments—or myofilaments—arranged in a characteristic pattern (described below). Thin bands are primarily composed of the protein actin whereas thick filaments contain primarily the protein myosin.3

When visualized under light microscopy, each repeating unit of protein filaments—known as a sarcomere—appears as alternating dark and light bands. Briefly, each sarcomere is demarcated by two dark lines (Z-lines) which serve as anchor points for actin molecules. The Z-line is in turn flanked by the I-band, which corresponds to the zone containing thin filaments without any overlapping thick filaments. The area between two I-bands is known as the A-band, which spans the entire length of a thick filament. The area within the A-band containing thick filaments without any overlapping thin filaments is known as the H-zone. Finally, the M-line is at the center of each sarcomere and contains important support proteins. T tubules (described above), surround myofibrils at two points in each sarcomere: at the junction of the A- and I-bands.

Apart from the main contractile proteins described above, hundreds of skeletal muscle proteins have been identified, with functions including structural support, excitation-contraction coupling, generation of force, and more.4 A detailed description of every structural and functional skeletal muscle protein is beyond the scope of this review.

Excitation-contraction coupling

After an action potential arrives at a muscle cell via the neuromuscular junction, membrane depolarization at the triad region leads to activation of L-type Ca2+ voltage-gated channels, also known as the dihydropyridine channel (DHPR). Mechanical coupling between the DHPR and the ryanodine receptor (RYR), located at the terminal cisternae, leads to opening of the RYR and release of Ca2+ into the sarcoplasm. Even though the DHPR is both a voltage sensor and a Ca2+ ion channel, extracellular influx of Ca2+ via the DHPR is not necessary for release of Ca2+ from the sarcoplasmic reticulum.2 As we will discuss in the next section, a rise in intracellular [Ca2+]i is the primary signal that triggers the contraction of skeletal muscle.5,6

Termination of muscle contraction is accomplished by the removal of calcium from the sarcoplasm. Reuptake of calcium into the sarcoplasmic reticulum, mediated by the sarcoplasmic and endoplasmic reticulum Ca2+-ATPase (SERCA), is the primary mechanism by which muscle cells maintain calcium homeostasis after contraction. SERCA activity is inhibited by rising [Ca2+]i inside the sarcoplasmic reticulum. Calsequestrin, a calcium-binding protein found in the lumen of terminal cisternae, buffers the increase in [Ca2+]i in the sarcoplasmic reticulum and allows for increased calcium-storing capacity.2

Cross-bridge cycle

The mechanism by which a rise in intracellular [Ca2+]i leads to a contractile force is explained by the sliding filament theory, which can be roughly divided into five steps. First, binding of Ca2+ to the troponin C molecule induces a conformational change in the tropomyosin molecule, allowing the attachment of the myosin head at the myosin binding site on the actin filament. Binding of ATP to the myosin head reduces its affinity for actin, resulting in their dissociation (Step 1). Hydrolysis of ATP into ADP and inorganic phosphate (Pi) by the myosin ATPase enzyme induces a conformational change in the myosin head into the “cocked” position (Step 2). The “cocked” myosin, which also contain the products of ATP hydrolysis, is now able to bind to a new position on the actin filament (Step 3). Contrary to the myosin-ATP complex, the myosin-ADP-Pi complex has high affinity for actin. Release of Pi from the myosin head triggers the power stroke; a conformational change that pulls the actin filament over the myosin filament, generating force and movement (Step 4). Finally, ADP is released from the myosin head, leaving the actin-myosin complex in the rigid state (Step 5). The complex remains bound until another molecule of ATP binds, initiating another cycle.7

As described above, separation of the actin-myosin complex is dependent on ATP. Depletion of ATP reserves and cessation of metabolism, as seen soon after death, leads to a state of extreme muscle rigidity known as rigor mortis. In this scenario, termination of muscle contraction is only limited by eventual protein and muscle fiber degradation.

Skeletal muscle fiber types

Despite similar architecture, there are important differences in the biochemical, mechanical, and metabolic properties of individual muscle fibers. This heterogeneity allows for muscles to serve different functional purposes, with different demands for strength, speed, and endurance.

Using histochemical staining for myosin ATPase activity, skeletal muscle fibers have been traditionally classified as slow-twitch (type 1) or fast-twitch (type 2). Current nomenclature, based on differential myosin heavy chain (MyHC) gene expression, further classifies type 2 fibers into three major groups: type 2A, 2X and 2B. Physiologic studies of single fiber have shown that MyHC distribution correlates with speed of contraction, which progressively increases from type 1 (slowest) to type 2A, 2X and 2B (fastest).8,9 Our discussion on fast-twitch fibers will be limited to type 2A and 2X fibers, as humans do not appear to have MYH4-expressing type 2B fibers.9

Metabolically, whereas slow-twitch muscle fibers have abundant mitochondrial density and rely on oxidative phosphorylation, fast-twitch fibers exhibit heightened glycolytic enzyme activity.8,9 Fiber-specific expression of muscle proteins such as SERCA, troponin subunits, tropomyosin, and C protein also contributes significantly to the distinctive contractile and relaxation properties of muscle fibers, particularly concerning calcium ion (Ca2+) responsiveness.10 Table 1 summarizes important differences between slow- and fast-twitch fibers.

Skeletal-Muscle-Physiology-Table-1

Relevance to Clinical Practice

The importance of proper structure and function of the musculoskeletal system is underscored by the wide range of neuromuscular diseases that have been identified. Broadly, neuromuscular diseases can be classified as motor neuron diseases, disorders of neuromuscular transmission, muscular dystrophies, metabolic and mitochondrial myopathies, peripheral neuropathies, and non-dystrophic myotonia. Table 2 offers a limited classification overview of select neuromuscular diseases

Even though an in-depth description of every muscle pathology is beyond the scope of this article, some disorders will be briefly discussed to highlight how alterations in both structure and function can lead to disease processes.

Skeletal-Muscle-Physiology-Table-2

Duchenne muscular dystrophy

Duchene muscular dystrophy (DMD), an X-linked recessive genetic disorder, is the most common muscular dystrophy of childhood. Dystrophin deficiency has been established as the cause of DMD and other diseases—collectively known as dystrophinopathies—. Dystrophin is part of an important support complex that connects the cytoskeleton of muscle fibers with the extracellular matrix, increasing fiber strength and stability. Absent dystrophin brings about a complex cascade of intracellular events leading to muscle fiber destruction and infiltration by adipose and connective tissue. The disorder is characterized by progressive muscle degeneration and weakness causing difficulty with basic mobility. In its late stages, acute respiratory failure can occur due to respiratory muscle weakness.11 Despite increased understanding of the cellular and molecular basis of DMD, a cure has not been identified. Research on novel therapeutic approaches is in process and has shown promising results.12

Dermatomyositis and polymyositis

Dermatomyositis and polymyositis are both rare autoimmune diseases that belong to the category of inflammatory myopathies, characterized by muscle inflammation and weakness. However, they differ in several key aspects, including their pathogenesis, clinical presentation, and diagnostic criteria (Table 3).

Skeletal-Muscle-Physiology-Table-3

Sarcopenia and frailty

Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass and strength with increased risk of physical disability, poor quality of life and death.13 The correlation between poor muscle function—specifically grip strength— and increased all-cause mortality rates in older people underscores the importance of sarcopenia as an important modifiable risk factor in this population. Current guidelines recommend documentation of both low muscle mass and low muscle function (i.e., strength or performance) for the diagnosis of sarcopenia.13 In practice, sarcopenia may be classified as primary (age-related) or secondary (activity-, disease-, or nutrition-related).

Although related to sarcopenia, frailty is a broader syndrome resulting from age-related decline across multiple physiologic systems with increased vulnerability to stressors.14 Risk factors for the onset and progression of frailty span across a wide range of sociodemographic (e.g., female sex, low socioeconomic position, loneliness), clinical (e.g., chronic diseases, obesity, impaired cognition, polypharmacy), lifestyle (e.g., physical inactivity, smoking, alcohol intake), and biological factors (e.g., inflammation, vitamin deficiency, androgen deficiency).14 Having frailty increases the likelihood of experiencing adverse outcomes, such as falls, hospitalizations, and death.

Recognizing the intricate relationship between muscle structure and function with these conditions is crucial for developing effective prevention and management strategies.15 Promoting healthy aging involves not only maintaining physical function but also addressing psychosocial factors to enhance the overall quality of life for older adults.

Steroid-induced myopathy

Steroid myopathy is a condition characterized by muscle weakness and wasting, resulting from prolonged or high-dose corticosteroid use. It can be caused by either an excessive production of endogenous corticosteroids or the use of exogenous corticosteroids, often prescribed for conditions like asthma or inflammatory diseases.

Although the exact mechanism behind steroid-induced myopathy remains unclear, several factors are believed to contribute to its development. Corticosteroids can promote the breakdown of muscle proteins while inhibiting muscle protein synthesis, leading to muscle atrophy and weakness. Additionally, steroids may impair the function of muscle cells, disrupt neuromuscular transmission, alter mitochondrial function, and induce changes in muscle fiber type.16

Diagnosing steroid-induced myopathy can be challenging because its symptoms can overlap with those of the underlying medical condition for which steroids are prescribed. Laboratory studies (e.g., serum and urine creatine kinase, myoglobinuria), muscle biopsy, electrodiagnostic studies, and muscle ultrasonography are all part of the evaluation of a patient with suspected steroid-induced myopathy.

Critical illness myopathy

Critical illness myopathy (CIM) is a frequent complication of severe illness, particularly in patients admitted to intensive care units. CIM manifests as diffuse weakness and is associated with delayed recovery, difficulty weaning from mechanical ventilation, and prolonged hospitalizations. To date, the underlying mechanism leading to CIM is not fully understood. The pathogenesis is likely multifactorial and proposed mechanisms include microvascular dysfunction, metabolic alterations, electrical abnormalities and bioenergetic failure.17,18 Sepsis, multiple organ failure, parenteral nutrition, and administration of high-dose corticosteroids have been suggested as important risk factors for the development of CIM.19

The Medical Research Council (MRC) sum score is often used as a screening tool for patient with suspected CIM.18 The MRC scores individual muscles on a scale ranging from 0 to 5 (Table 4). MRC sum scores can range from 0 to 60 where a score below 48 is suggestive of ICU-acquired weakness. Because not all patients with CIM have muscle necrosis, traditional laboratory tests for myopathies (e.g., serum creatine kinase) are unreliable. Available diagnostic tools include electrodiagnostic studies, direct muscle stimulation, and muscle biopsy. Although both preventive and supportive therapies may be beneficial, no definitive preventive, diagnostic or therapeutic strategies exist for patients with CIM.

Skeletal-Muscle-Physiology-Table-4

Response to exercise

As described above, skeletal muscle fibers are classified based on their myosin heavy chain (MyHC) isoform and contractile speed. Both approaches show that, in addition to pure fiber types, skeletal muscle contains variable MyHC composition, allowing their function to be task-specific.8 Further, skeletal muscles can undergo adaptive and maladaptive changes in response to use and disuse, including conversion between fiber types. An important example of this remarkable adaptability of skeletal muscle occurs in response to exercise.

Exercise, particularly resistance training and endurance training, can trigger changes in the composition of muscle fiber types within a muscle. This phenomenon, known as muscle fiber type switching or muscle plasticity, allows muscles to adapt to the specific demands imposed by training. Endurance training (e.g., long-distance running or cycling) primarily relies on slow-twitch (type 1) muscle fibers. Over time, endurance training can lead to an increased proportion of type 1 muscle fibers within a muscle. Conversely, resistance training (e.g., weightlifting or sprinting) primarily stimulates type 2 muscle fibers. As a response to resistance training, muscles may undergo both hypertrophy (increased size) and a shift towards a greater proportion of type 2 muscle fibers.20

The specific mechanism for this phenomenon is not completely understood but current evidence suggests that a combination of genetic, training, nutrition, and lifestyle factors appear to interact and influence individual fiber type distribution.20 Beyond the scope of this review, future research will help to elucidate differences in fiber type plasticity in different muscles, regional specificity, long-term adaptability, and other practical considerations, such as nutritional and training strategies.

Malignant hyperthermia

Malignant hyperthermia (MH) is an autosomal dominant disorder of skeletal muscle caused by impaired Ca2+ homeostasis following exposure to halogenated anesthetics or depolarizing muscle relaxants. Cases have also been described in response to physical stressors (e.g., vigorous exercise or heat exposure). MH occurs due to a defect in the Ca2+-release channel (RYR) which leads to exaggerated release of calcium from the sarcoplasmic reticulum upon exposure to a triggering agent. Abnormally elevated intracellular [Ca2+] causes sustained muscle contraction and ATP depletion, which ultimately leads to sarcolemmal membrane failure and release of toxic intracellular contents into the blood stream.21 Dantrolene, a RYR antagonist, blocks EC coupling and reduces the release of calcium from the sarcoplasmic reticulum and is the only specific therapy for MH.

Cutting Edge Concepts & Emerging Issues

The prospect of targeted genome-editing has emerged as a promising therapeutic approach for many neuromuscular diseases with well-documented causative genetic mutations.22,23 As the most common muscular dystrophy, much of the research efforts have focused on DMD. Indeed, the drug development pipeline is full of potential treatments aimed at curing or ameliorating the devastating consequences of DMD.11 Broadly, therapeutic approaches being studies include: (1) restoring or replacing dystrophin,24 (2) reducing inflammation,25 (3) calcium homeostasis,26 (4) improving muscle growth and protection,27 (5) restoring mitochondrial activity, and (6) improving heart function. In theory, replacing the mutated dystrophin gene would cure the disease. Efforts have been limited due to the large size of the dystrophin gene, which exceeds the capacity of current delivery systems. To this end, a smaller version of the gene—micro-dystrophin—has been engineered to produce a functional protein.28,29 Studies in animal models have shown promising results and several clinical trials are in process evaluating the safety, tolerability and efficacy of micro-dystrophin gene transfer in patients with DMD. Clinical trials are also in process for the therapeutic approaches described earlier. Casimersen, an exon skipping drug, is the latest therapeutic to receive FDA approval for use in DMD patients with specific dystrophin gene mutations.30

Briefly, the CRISPR-Cas9 system has revolutionized the field of genome-editing and is particularly promising for neuromuscular diseases.31-34 The system is able to recognize and remove specific DNA sequences, allowing for targeted renewal or replacement. Although in its early clinical stages, in-vitro and animal models have shown promising results for correcting the defective dystrophin gene.35

Gaps in Knowledge/Evidence Base

Despite significant progress in recent years, the cellular and molecular underpinnings of skeletal muscle physiology and pathophysiology are not fully understood. Further research is needed on the role of skeletal muscle as an endocrine organ, transcriptional and post-transcriptional regulation of gene expression, bioenergetics, and protein turnover—among other concepts—. This will help us better understand the molecular basis for the adaptive and/or maladaptive responses of skeletal muscle in health and disease.

References

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Author Disclosure

William A. Ramos-Guasp, MD
Nothing to Disclose

Edwardo Ramos, MD
Nothing to Disclose