Excitation-contraction coupling is the mechanism by which neural action potentials convert to cross-bridge cycling, i.e., contraction. Action potentials of the motor neuron cause release of acetylcholine (ACh) from the neuron terminus at the neuromuscular junction, or motor end plate. The ACh causes depolarization at the neuromuscular junction and transmits the action potential to the muscle fiber. Action potentials create muscle contraction through excitation-contraction coupling. In this process, action potentials travel along the cell membrane and into the T tubules to carry the signal to the interior of the muscle fiber. Depolarization causes a conformational modification in the dihydropyridine receptors of the T tubules, with or without calcium (Ca) influx. This conformational change opens ryanodine receptors on the terminal cisternae of the sarcoplasmic reticulum to release Ca from storage in the sarcoplasmic reticulum into the intracellular fluid (ICF), increasing the concentration of ICF Ca by a factor of 10 (from 10 to 10 M). The increased ICF concentration of Ca causes a conformational change of the troponin complex by binding troponin C on the actin filament. Each troponin C can bind a maximum of 4 Ca ions, and binding is cooperative in nature (similar to hemoglobin binding of oxygen), which allows a small change in [Ca] to saturate the troponin C binding sites. The conformational change of troponin C uncovers the myosin binding sites on actin by pulling tropomyosin out of the way, which begins the cross-bridge cycling that causes skeletal muscle contraction. After excitation and subsequent depolarization of the T tubules ceases, Ca is released from troponin C and sequestered by the sarcoplasmic reticulum in the terminal cisternae through a CaATPase in the membrane of the sarcoplasmic reticulum known as SERCA. Sequestration of Ca allows tropomyosin to cover the myosin binding sites on actin, which causes relaxation of the muscle.[2]

Cross-bridge cycling is the mechanism by which skeletal muscle contracts. At the beginning of this cycle, myosin is bound tightly to actin in a step termed rigor. In the absence of basic physiologic energy, adenosine triphosphate (ATP), such as in death this is a semi-permanent state called rigor mortis. In living tissue, this is a transient state, as ATP binding by the myosin head causes a conformational change of the myosin head that causes the release of the actin-myosin cross-link. After ATP is bound and the cross-link released, ATP is hydrolyzed to adenosine diphosphate (ADP) and inorganic phosphate, “re-cocking” and moving the myosin head toward the positive end of actin (closer to the ends of the sarcomere). As long as there is adequate Ca to maintain an uncovered actin binding site, the myosin head will form a cross-bridge with actin. The release of ADP and inorganic phosphate causes the power stroke where the myosin head moves toward the – end of actin (toward the center of the sarcomere), displacing the actin filament and shortening the sarcomere. To complete the cycle, ADP is released, and the sarcomere returns to a state of rigor. This cycle repeats as long as Ca is bound to troponin C.[3]

The force of contraction is a summation of the number of motor units recruited and the frequency of action potentials that reach those motor units. The motor unit is a single neuron and all the muscle fibers it innervates. The number of muscle fibers comprising a motor unit depends on the function of the muscle; muscles that require fine motor control will involve fewer fibers whereas larger muscle groups will involve significantly more muscle fibers. Muscles that function over a prolonged period, such as lower back muscles, will asynchronously recruit fibers so that fatigue of individual fibers is spread out over time and space. Tension on a whole muscle scale is a result of the additive tension of individual muscle fibers. Recruitment of muscle fibers occurs when an action potential causes the release of a fixed amount of Ca from the sarcoplasmic reticulum, which produces a single muscle twitch followed by sequestration for calcium. Continual stimulation of the muscle by further action potentials causes further release of calcium, and summation of twitches, which allows the muscle to continue contracting. Maximal contraction occurs in a process called tetany when all Ca binding sites are in use, and all myosin binding sites remain uncovered.[4]

Cleavage of ATP to ADP and inorganic phosphate provides the energy needed both for the power stroke mechanism by which skeletal muscle contracts and reuptake of Ca by the terminal cisternae. ATP stores within the muscle rapidly deplete, so ATP must be regenerated. The first mechanism for ATP generation within the muscle is the transfer of a phosphate group from creatine phosphate to ADP. Upon the depletion of creatine phosphate stores, ATP production comes via by the citric acid cycle and the electron transport chain. Oxygen becomes the limiting factor in actively contracting muscle, and glycolysis alone, and subsequent conversion of pyruvate to lactate, later becomes the primary source of ATP generation for muscles.[5]

Neuromuscular spindles are present within skeletal muscles and function in proprioception. Intrafusal fibers, or the neuromuscular spindles, are found interspersed among extrafusal fibers. Intrafusal fibers are composed of two separate cells known as the nuclear bag fiber and the nuclear chain fiber. The entire unit functions partly as a muscle in that the fibers can contract and partly as a sensory receptor for length, tension, and rate of contraction. Primary afferent nerve fibers have annulospiral endings around both the bag and chain fibers and sense muscle length and rate of contraction. Secondary afferent fibers have flower spray endings, mostly on chain fibers, and function to sense muscle length.[6]

The pathophysiology involving skeletal muscle, while quite varied, may involve either the excitation-contraction coupling mechanism or the skeletal muscle itself. Because of the sheer mass of skeletal muscle in the human body as well as the vital breathing function of the diaphragm, conditions affecting skeletal muscle can become life-threating issues. 

Myasthenia gravis is an autoimmune disorder that results from antibodies to the ACh receptors of the neuromuscular junction. These antibodies prevent ACh from binding and decrease the amount of depolarization transmitted to the muscle cell. As repetitive use consumes ACh stores, lower concentrations of ACh released into the NMJ are not able to saturate the binding sites and produce an action potential within the muscle. In the patient, this presents as a variable weakness that is worse with use and better with rest. Often, the extraocular muscles are the first muscles affected in the course of the disease. Edrophonium, a short-acting acetylcholinesterase inhibitor, can be used in the diagnosis of myasthenia gravis. When administered, it prolongs the action of ACh at the NMJ and prevents muscle fatigue for a short time.[7]

Toxins may also affect excitation-contraction coupling at the NMJ. Botulism toxin, produced by C. botulinum, inhibits the release of ACh from the presynaptic neuron at the NMJ, preventing excitation of skeletal muscle and causing a flaccid paralysis. Tetanospasmin, a neurotoxin released by C. tetani, prevents relaxation through blockage of inhibitory neurotransmitter release by interneurons that synapse at the NMJ which leads to spastic paralysis.[8] 

Rhabdomyolysis is a direct injury to the architecture of skeletal muscle, leading to the release of intracellular contents such as electrolytes and myoglobin to the extracellular space. The insults leading to skeletal muscle injury are numerous and beyond the scope of this article, but some examples include overuse (e.g., marathon), compartment syndrome, and use of prescription, over the counter, and illicit drugs. The cellular insult is a direct result of the release of large amounts of ionized calcium from the terminal cisternae, which activates degradation processes. The downstream effects of rhabdomyolysis are systemic and life-threatening.[9] 

Atrophy of skeletal muscle may result from many things, including disuse, denervation, systemic illness, chronic glucocorticoid use, and malnourishment. While the pathways may differ, in all of these cases, atrophy is caused by increased proteolysis mediated by the ubiquitin system and decreased protein synthesis, which reduces muscle mass by reducing the diameter of individual muscle fibers.[10]

The clinical course of disease processes affecting skeletal muscle varies ranging from imperceptible to life-threatening even within the course of the same disease. Myasthenia gravis typically presents as progressive weakness due to antibodies against ACh receptors at the NMJ that interferes with propagation of the action potential; this manifests as a weakness that impedes any muscle activity.  The disease process may affect activities of daily living including an impact on the forms of work the patient is able to perform. On the more severe end of the spectrum, however, myasthenic crises are life-threatening episodes that require emergent treatment to ensure the patient does not stop breathing as intercostal muscles are affected as well as larger muscle groups such as in the legs and arms.

Rhabdomyolysis is a skeletal muscle condition that can range in its impact from mild discomfort to lethal. The presentation of patients with rhabdomyolysis depends on several factors including the size of the initial insult, the patient's previous state of health, and whether muscle injury is direct or indirect. Symptoms may include myalgias or red to brown urine, but the absence of these findings is not enough to rule out the condition. Rhabdomyolysis may also present with the nonspecific symptoms of nausea, vomiting, fever, and fatigue. The clinician should elicit a thorough history to determine risk factors such as trauma, recent exertional strain, and medication use. Serial measurements of creatine kinase, a biomarker for muscle damage, and electrolytes should be obtained to monitor the development of rhabdomyolysis and response to therapy. Unlike myasthenia gravis, rhabdomyolysis may prove to be fatal through organ systems other than the skeletal muscle that is primarily affected.  The damage to the skeletal muscle can lead to breakdown products that impede kidney function and in severe cases can lead to acute renal failure requiring dialysis to prevent death.