Skeletal Muscle

Skeletal Muscle: Structure, Function, Energetics, Injury, and Repair

General Information

Skeletal muscles are innervated by the peripheral nervous system. They provide voluntary movement of the axial and appendicular skeleton. A motor unit consists of a single motor neuron and the muscle fibers it innervates.

Hierarchical Structure of Muscle

A muscle fiber is a multinucleated, highly specialized cell. The contractile unit is the sarcomere. Sarcomeres are aligned in series to form myofibrils. Mechanical coupling between myofibrils is provided by intermediate filaments. Each fiber is surrounded by endomysium, fascicles by perimysium, and the whole muscle by epimysium.

Membrane Systems

The T-tubule system originates as invaginations of the sarcolemma and transmits excitation to myofibrils. The sarcoplasmic reticulum stores, releases, and reuptakes calcium. The T-tubule and two adjacent terminal cisternae form the “triad” structure. This arrangement enables rapid and synchronized activation of contraction.

Composition and Organization of the Sarcomere

The thick filament is myosin; the thin filament is actin. Tropomyosin covers myosin-binding sites on actin in the resting state. Upon calcium binding, the troponin complex induces a conformational shift of tropomyosin, initiating actin–myosin interaction. The A band (actin + myosin), I band (actin), H band (myosin), and Z line create the typical striation pattern. During contraction, the sarcomere shortens; filament lengths remain constant, but overlap increases.

Neuromuscular Junction (NMJ) and Transmission

Each muscle fiber is activated by a single motor endplate. Acetylcholine (ACh) is released from the presynaptic terminal, activates postsynaptic receptors, and generates an action potential. The impulse propagates via the T-tubule/SR network. ACh is rapidly degraded by acetylcholinesterase. Transmission can be modulated pharmacologically:
– Non-depolarizing agents competitively block receptors.
– Depolarizing agents (succinylcholine) cause persistent depolarization.
– AChE inhibitors prolong transmission by preventing ACh degradation.
Myasthenia gravis is characterized by a reduction in postsynaptic ACh receptors.

Mechanical Responses of Muscle

A single stimulus produces a “twitch” response. Repeated stimuli lead to temporal summation and tetanus. Force is proportional to the physiological cross-sectional area; fiber length and pennation angle are also determinants. Types of contraction: isotonic, isokinetic, isometric; concentric (shortening) and eccentric (lengthening) behaviors occur. According to the force–velocity relationship, eccentric contraction produces the greatest tension and carries higher risk of injury.

Fiber Types and Performance

Type I fibers are slow, oxidative, and fatigue-resistant. Type IIA fibers display intermediate properties. Type IIB fibers are fast, glycolytic, and fatigue rapidly. Training can modify distribution and oxidative capacity; endurance training increases mitochondrial content and oxidative enzyme activity.

Energy Systems
Skeletal muscle contraction is fueled by three main pathways:

1. Phosphagen      system: Provides very short-term, anaerobic energy via ATP and      creatine phosphate.

2. Anaerobic      glycolysis: Produces lactate from glucose, supporting 20–120 seconds      of high-intensity activity.

3. Aerobic      metabolism: Krebs cycle and oxidative phosphorylation yield high ATP      output; fat and protein substrates can also be utilized. Endurance      training enhances oxidative efficiency and promotes fat utilization.

Muscle Injury and Repair

Repair is mediated by cytokines released from neutrophils, monocytes/macrophages, fibroblasts, and endothelial cells. Necrotic fibers are cleared by macrophages. The source of regeneration is satellite cells, which are activated upon injury. Concurrent fibrosis can limit full functional recovery. Delayed-onset muscle soreness (DOMS) arises 24–72 hours after eccentric loading; edema and increased intramuscular pressure are implicated. Contusions involve hematoma, inflammation, and variable regeneration; myositis ossificans may develop within 2–4 weeks. Muscle strains typically occur at the myotendinous junction in muscles crossing two joints; incomplete tears show early inflammation and force reduction with recovery within a week (experimental data). Complete ruptures present with contour deformity. Healing after laceration usually results in scar tissue; regeneration and reinnervation are limited. Denervation manifests within 2–4 weeks with fibrillation potentials and increased ACh sensitivity.

Immobilization and Disuse

Rapid atrophy, loss of strength, and increased fatigability occur. Myofibrillar loss is the main cellular finding. The length at which the muscle is immobilized is important: atrophy is greater in a slack position (e.g., quadriceps in knee extension). Muscles held under stretch add new sarcomeres, partially compensating for atrophy, although cross-sectional area continues to decrease.

Clinical Implications

Selection of anesthetics and neuromuscular blockers is based on NMJ physiology. Eccentric loading should be appropriately dosed in rehabilitation. Early and adequate loading supports mitochondrial and oxidative adaptations. Timing of inflammation and duration of immobilization are critical in limiting fibrosis and optimizing satellite cell response after injury.

Summary

This overview presents the cellular and mechanical foundations of skeletal muscle, its energy utilization, adaptive responses, and the dynamics of injury and repair in relation to clinical decision-making.

References

1. Jin JB, Zhao D, Wu H, et al. Metabolic and molecular regulation in skeletal muscle function and regeneration. Front Cell Dev Biol.  .doi:10.3389/fcell.2025.1651553

2. Yeowell GJ, Dunbar PJ, Carré MJ, Tarsuslugil A, Mason PH, Hennessey P. Molecular mechanisms of muscle wasting in muscle disuse, denervation, and chronic disease. J Cachexia Sarcopenia Muscle. 2023;14(3):799–815. doi:10.1002/jcsm.13098

3. Brorson J, Lin L, Wang J, et al. Complementing muscle regeneration—fibro-adipogenic progenitor and macrophage-mediated repair of elderly human skeletal muscle. Nat Commun. 2025;16:5233. doi:10.1038/s41467-025-60627-2