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Voluntary skeletal muscle contraction occurs when an electrical signal (action potential) travels via somatic nerves to the synaptic cleft. Here, the electrical action potential opens voltage-gated calcium channels, and calcium causes the release of acetylcholine (ACh) into the synaptic cleft. The ACh travels across the synaptic cleft binding to nicotinic ACh receptors, which when activated, allow an influx of sodium ions into the muscle fiber membrane. The intracellular voltage change from the influx of sodium transmits an action potential via T-tubules to the center of the muscle cell, where on reaching the sarcoplasmic reticulum, calcium ions are released, enabling muscle fibers to contract.

Skeletal muscle is composed of muscle fascicles, which in turn comprises a group of muscle fibers. A muscle fiber has thick filaments made of myosin, and thin filaments made of actin, troponin, and tropomyosin. Myosin heads have two types of binding sites; actin and adenosine triphosphate (ATP). For contraction to occur, both must be occupied. Binding sites on actin unit are blocked by the protein tropomyosin. The inflowing calcium from the sarcoplasmic reticulum binds to troponin, which changes conformation of tropomyosin, thus exposing actin-binding sites, and ultimately allowing myosin to bind to actin. Relaxation requires sequestration of calcium back into the sarcoplasmic reticulum, as well as an additional molecule of ATP.

Muscle contraction can be inhibited by blocking postsynaptic ACh receptors. Nondepolarizing muscle relaxants are competitive antagonists of ACh, whereas succinylcholine is a competitive agonist. Both bind to the postsynaptic nicotinic ACh receptor. Succinylcholine causes a depolarization of the muscle, seen clinically as muscle fasciculation.


Malignant hyperthermia manifests when a triggering agent (inhalational agents, succinylcholine) causes massive release of calcium from the sarcoplasmic reticulum in susceptible individuals. This results in gross uncoordinated muscle fasciculation, and generates heat, raising body temperature. Muscle breakdown can result in rhabdomyolysis, and myoglobin released from damaged muscle can lead to renal failure. Treatment of a malignant hyperthermic episode includes dantrolene, which depresses excitation–contraction coupling of skeletal muscle.

Myasthenia gravis is an autoimmune disease where antibodies destroy nicotinic ACh receptors in the neuromuscular junction, leading to fluctuating muscle weakness, and increased muscle fatigue after activity.

Lambert–Eaton myasthenic syndrome is also an autoimmune disease, where antibodies are developed against presynaptic voltage-gated calcium channels. It manifests as limb weakness that improves with activity.


  • Muscle contraction: Actin and myosin

  • Skeletal mm: Contraction mechanism


Matthew de Jesus, MD contributed to this chapter in the first edition and some material from that chapter has been retained here.

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