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Physiology, Skeletal Muscle

Physiology, Skeletal Muscle

Article Author:
Christopher McCuller
Article Author:
Rishita Jessu
Article Editor:
Avery Callahan
8/22/2020 11:02:54 PM
For CME on this topic:
Physiology, Skeletal Muscle CME
PubMed Link:
Physiology, Skeletal Muscle


Skeletal muscle is found throughout the body and functions to contract in response to voluntary stimulus. Skeletal muscle serves many purposes including maintaining body posture, moving the body and objects, beginning the swallow reflex, and changing thoracic volume to inhale or exhale. Unlike smooth muscle and cardiac muscle, skeletal muscle receives neural input that allows conscious control of the muscles.


Skeletal muscle is composed of many cells, referred to as muscle fibers ranging from 10 to 80 mm in diameter. Most fibers span the length of the muscle. These cells are multinucleate cells with nuclei found at the periphery of the cell. Most muscle fibers receive innervation from a single nerve near the middle of the muscle fiber. The sarcolemma encases each muscle fiber. 

The plasma membrane and a polysaccharide coating that fuses with tendon fibers comprise the sarcolemma. The sarcolemma invaginates within the muscle fiber to form deep T-tubules (transverse tubules). These T-tubules converge within the cell and are a major location for ion exchange. Covering the sarcolemma is a connective tissue covering called the endomysium.  Capillaries to supply the fibers and nerve tissue to that individual fiber are present in the endomysium. Each muscle fiber joins with other muscle fibers forming fascicles which are encased by a connective tissue covering known as the perimysium. The fascicles further group to form a muscle, which is encased by the epimysium.

Each muscle fiber is composed of several hundred to several thousand myofibrils.  Myofibrils are composed of actin (thin filaments) and myosin (thick filaments) along with support proteins. The arrangement of actin and myosin gives skeletal muscle its microscopic striated appearance and creates functional units called sarcomeres. The sarcomeres are arranged longitudinally and include the M line, Z disk, H band, A band, and I band when viewed under electron microscopy. The Z line, or Z disk, is the terminal boundary of the sarcomere where alpha-actinin acts as an anchor for the actin filaments. The M line is the central-most line of the sarcomere where myosin filaments are anchored together through binding sites within the myosin filament. The H band contains the M line and is the central region of the sarcomere that contains only myosin filaments. The A band is a larger portion of the sarcomere that contains the entirety of the myosin fibers and includes regions of actin and myosin overlap. The I band covers the terminal regions of two adjacent sarcomeres and contains only actin filaments. Both the H band and I band shorten with muscle contraction, while the A band is a constant length.

Actin filaments are double helical structures, known as F-actin, and are composed of monomeric units of G-actin. G-actin exhibits polarity and creates a positive and negative end within the sarcomere, with the positive end situated toward the terminal end of the sarcomere. Tropomyosin is a helical protein that runs along the actin double helix within its groove. Troponin binds tropomyosin by a troponin complex at every 7 actin monomer and is composed of troponin-C (Tn-C), troponin-I (Tn-I), and troponin-T (Tn-T). Tn-T binds tropomyosin, Tn-I inhibits the binding of actin and myosin, and Tn-C binds calcium. Myosin proteins are composed of two regions: light meromyosin and heavy meromyosin. Light meromyosin binds other light meromyosin regions to anchor myosin at the M line. Heavy meromyosin, is further subdivided into two regions, the S-1 portion, or the myosin head, binds actin and contains an ATPase portion while the S-2 portion is the location of the power stroke.

Support proteins within the sarcomere include titin, desmin, myomesin, C protein, nebulin, and plectin. Plectin tethers the Z disks of adjacent myofibrils to each other. Desmin helps to maintain myofibril alignment, and also connects to the cytoskeleton and other structural elements within the cell and functions to distribute contractile force. Myomesin and C protein are both myosin binding proteins that function to tether and stabilize myosin at the M line. Titin is found at the Z disk and anchors myosin longitudinally within the sarcomere.

There are three types of muscle fibers. Type I fibers, or slow oxidative fibers, are slow-twitching fibers that obtain ATP primarily from oxidative phosphorylation. The myosin heads cleave ATP more slowly than the other two types of fibers and are best suited for endurance types of contraction. Type IIa fibers, or fast oxidative fibers, are a faster twitching fiber used for intermediate endurance contractions. Both types I and IIa fibers are considered red fibers and contain high numbers of mitochondria, as well as the protein myoglobin, which confers the red coloration to the fibers. Type IIb fibers, or fast glycolytic fibers, are the fastest twitching fibers that produce the greatest force for the shortest amount of time. They considered white fibers with low levels of myoglobin and a high concentration of glycolytic enzymes and glycogen stores since they produce ATP primarily from glycolysis. Type IIb fibers are also the largest diameter fibers because they have the highest density of actin and myosin proteins.


Skeletal muscle derives from mesodermal tissue that originates in the somite. As development progresses, the lateral mesoderm forms and matures further to become the epaxial and hypaxial dermomyotome. The dermomyotome eventually differentiates to the skin of the back and the skeletal muscle of the body and limbs. The epaxial dermomyotome eventually becomes the deep muscles of the back, and the hypaxial dermomyotome eventually becomes the rest of the muscles of the body and limbs.

In a process called delamination, epithelial cells of the hypaxial mesoderm dissociate from the mesodermal tissue, which is followed by migration to the limbs. The transcriptional activation of c-met by Pax3 mediates the process of delamination. The c-met product then charts the course for migration of hypaxial cells. Lbx1 is also thought to affect migration as a transcription factor, but its target is currently unknown.

Once the migrating cells have reached their destination, proliferation and myogenesis begin. Proliferation is thought to occur before and after differentiation and appears to be influenced by c-met, which is activated by Pax3, and Msx1. To initiate myogenesis, the cells begin expressing the determination factors MyoD and Myf5. Myogenin controls further differentiation, in addition to many other factors. Splitting of muscle masses into individual muscles is controlled by Lbx1 and Mox2.[1] 


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]

Clinical Significance

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.  


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