| Skeletal muscle | |
|---|---|
 Depiction of skeletal muscle | |
| Details | |
| Synonyms | Skeletal striated muscle, striated voluntary muscle |
| System | Muscular system |
| Identifiers | |
| Latin | muscularis skeletalis |
| MeSH | D018482 |
| TA2 | 1976 |
| TH | H2.00.05.2.00002 |
| Anatomical terminology | |
Skeletal muscle (commonly referred to asmuscle) is one of the three types ofvertebratemuscle tissue, the others beingcardiac muscle andsmooth muscle. They are part of thevoluntary muscular system[1] and typically are attached bytendons tobones of askeleton.[2][3] The skeletalmuscle cells are much longer than in the other types of muscle tissue, and are also known asmuscle fibers.[4] The tissue of a skeletal muscle isstriated – having a striped appearance due to the arrangement of thesarcomeres.
A skeletal muscle contains multiplefascicles – bundles of muscle fibers. Each individual fiber and each muscle is surrounded by a type ofconnective tissue layer offascia. Muscle fibers are formed from thefusion of developmentalmyoblasts in a process known asmyogenesis resulting in longmultinucleated cells. In these cells, thenuclei, termedmyonuclei, are located along the inside of thecell membrane. Muscle fibers also have multiplemitochondria to meet energy needs.
Muscle fibers are in turn composed ofmyofibrils. The myofibrils are composed ofactin andmyosin filaments calledmyofilaments, repeated in units called sarcomeres, which are the basic functional, contractile units of the muscle fiber necessary formuscle contraction.[5] Muscles are predominantly powered by theoxidation offats andcarbohydrates, butanaerobic chemical reactions are also used, particularly byfast twitch fibers. These chemical reactions produceadenosine triphosphate (ATP) molecules that are used to power the movement of themyosin heads.[6]
Skeletal muscle comprises about 35% of the body of humans by weight.[7] The functions of skeletal muscle include producing movement, maintaining body posture, controlling body temperature, and stabilizing joints.[8] Skeletal muscle is also anendocrine organ.[9][10][11] Under different physiological conditions, subsets of 654 different proteins as well as lipids, amino acids, metabolites and small RNAs are found in thesecretome of skeletal muscles.[12]
Skeletal muscles are substantially composed ofmultinucleated contractilemuscle fibers (myocytes). However, considerable numbers of resident and infiltrating mononuclear cells are also present in skeletal muscles.[13] In terms of volume, myocytes make up the great majority of skeletal muscle. Skeletal muscle myocytes are usually very large, being about 2–3 cm long and 100 μm in diameter.[14] By comparison, the mononuclear cells in muscles are much smaller. Some of the mononuclear cells in muscles[15] are endothelial cells (which are about 50–70 μm long, 10–30 μm wide and 0.1–10 μm thick),[16]macrophages (21 μm in diameter) andneutrophils (12-15 μm in diameter).[17] However, in terms of nuclei present in skeletal muscle, myocyte nuclei may be only half of the nuclei present, while nuclei from resident and infiltrating mononuclear cells make up the other half.[13]
Considerable research on skeletal muscle is focused on the muscle fiber cells, the myocytes, as discussed in detail in the first sections, below. Recently, interest has also focused on the different types of mononuclear cells of skeletal muscle, as well as on theendocrine functions of muscle, described subsequently, below.
There are more than 600 skeletal muscles in the human body, making up around 40% of body weight in healthy young adults.[18][19][20] In Western populations, men have on average around 61% more skeletal muscle than women.[21] Most muscles occur in bilaterally-placed pairs to serve both sides of the body. Muscles are often classed asgroups of muscles that work together to carry out an action. In thetorso there are severalmajor muscle groups including thepectoral, andabdominal muscles;intrinsic and extrinsic muscles are subdivisions of muscle groups in thehand,foot,tongue, andextraocular muscles of theeye. Muscles are also grouped intocompartments includingfour groups in the arm,and thefour groups in the leg.
Apart from the contractile part of a muscle consisting of its fibers, a muscle contains a non-contractile part of dense fibrous connective tissue that makes up thetendon at each end. The tendons attach the muscles to bones to give skeletal movement. The length of a muscle includes the tendons.Connective tissue is present in all muscles asdeep fascia. Deep fascia specialises within muscles to enclose each muscle fiber asendomysium; each muscle fascicle asperimysium, and each individual muscle asepimysium. Together these layers are calledmysia. Deep fascia also separates the groups of muscles into muscle compartments.
Two types ofsensory receptors found in muscles aremuscle spindles, andGolgi tendon organs. Muscle spindles arestretch receptors located in the muscle belly. Golgi tendon organs areproprioceptors located at themyotendinous junction that inform of amuscle's tension.
Skeletal muscle cells are the individual contractile cells within a muscle, and are often termed asmuscle fibers.[3] A single muscle such as thebiceps in a young adult male contains around 253,000 muscle fibers.[22]
Skeletal muscle fibers aremultinucleated with thenuclei often referred to asmyonuclei. This occurs duringmyogenesis with thefusion of myoblasts each contributing a nucleus.[23] Fusion depends on muscle-specific proteins known asfusogens calledmyomaker andmyomerger.[24]
Many nuclei are needed by the skeletal muscle cell for the large amounts of proteins and enzymes needed to be produced for the cell's normal functioning. A single muscle fiber can contain from hundreds to thousands of nuclei.[25] A muscle fiber for example in the human biceps with a length of 10 cm can have as many as 3,000 nuclei.[25] Unlike in a non-musclecell where the nucleus is centrally positioned, the myonucleus is elongated and located close to thesarcolemma. The myonuclei are quite uniformly arranged along the fiber with each nucleus having its ownmyonuclear domain where it is responsible for supporting the volume of cytoplasm in that particular section of the myofiber.[24][25]
A group of musclestem cells known asmyosatellite cells, alsosatellite cells are found between thebasement membrane and the sarcolemma of muscle fibers. These cells are normally quiescent but can be activated by exercise or pathology to provide additional myonuclei for muscle growth or repair.[26]
Muscles attach totendons in a complex interface region known as themusculotendinous junction, also known as themyotendinous junction, an area specialised for the primary transmission of force.[27] At the muscle-tendon interface, force is transmitted from the sarcomeres in the muscle cells to the tendon.[5] Muscles and tendons develop in close association, and after their joining at the myotendinous junction they constitute a dynamic unit for the transmission of force from muscle contraction to the skeletal system.[27]
Muscle architecture refers to the arrangement of muscle fibers relative to the axis offorce generation, which runs from amuscle's origin to itsinsertion. The usual arrangements are types ofparallel, and types ofpennate muscle. In parallel muscles, the fascicles run parallel to the axis of force generation, but the fascicles can vary in their relationship to one another, and to their tendons.[28] These variations are seen infusiform,strap, andconvergent muscles.[4] A convergent muscle has a triangular or fan-shape as the fibers converge at its insertion and are fanned out broadly at the origin.[28] A less common example of a parallel muscle is a circular muscle such as theorbicularis oculi, in which the fibers are longitudinally arranged, but create a circle from origin to insertion.[29] These different architectures, can cause variations in the tension that a muscle can create between its tendons.
The fibers inpennate muscles run at an angle to the axis of force generation.[29] Thispennation angle reduces the effective force of any individual fiber, as it is effectively pulling off-axis. However, because of this angle, more fibers can be packed into the same muscle volume, increasing thephysiological cross-sectional area (PCSA). This effect is known asfiber packing, and in terms of force generation, it more than overcomes the efficiency-loss of the off-axis orientation. The trade-off comes in overall speed of muscle shortening and in the total excursion. Overall muscle shortening speed is reduced compared to fiber shortening speed, as is the total distance of shortening.[29] All of these effects scale with pennation angle; greater angles lead to greater force due to increased fiber packing and PCSA, but with greater losses in shortening speed and excursion. Types of pennate muscle areunipennate,bipennate, andmultipennate. A unipennate muscle has similarly angled fibers that are on one side of a tendon. A bipennate muscle has fibers on two sides of a tendon. Multipennate muscles have fibers that are oriented at multiple angles along the force-generating axis, and this is the most general and common architecture.[29]
Muscle fibers grow when exercised and shrink when not in use. This is due to the fact that exercise stimulates the increase inmyofibrils which increase the overall size of muscle cells. Well exercised muscles can not only add more size but can also develop moremitochondria,myoglobin,glycogen and a higher density ofcapillaries. However, muscle cells cannot divide to produce new cells, and as a result there are fewer muscle cells in an adult than in a newborn.[30]
There are a number of terms used in the naming of muscles including those relating to size, shape, action, location, their orientation, and their number of heads.
Broadly there are two types of muscle fiber:Type I, which is slow, andType II which are fast. Type II has two divisions of type IIA (oxidative), and type IIX (glycolytic), giving three main fiber types.[33] These fibers have relatively distinct metabolic, contractile, andmotor unit properties. The table below differentiates these types of properties. These types of properties—while they are partly dependent on the properties of individual fibers—tend to be relevant and measured at the level of the motor unit, rather than individual fiber.[34]
| Properties | Type I fibers | Type IIA fibers | Type IIX fibers |
|---|---|---|---|
| Motor Unit Type | Slow Oxidative (SO) | Fast Oxidative/Glycolytic (FOG) | Fast Glycolytic (FG) |
| Twitch speed | Slow | Fast | Fast |
| Twitch force | Small | Medium | Large |
| Resistance to fatigue | High | High | Low |
| Glycogen content | Low | High | High |
| Capillary supply | Rich | Rich | Poor |
| Capillary density | High | Intermediate | Low |
| Myoglobin | High | High | Low |
| Red color | Dark | Dark | Pale |
| Mitochondrial density | High | High | Low |
| Oxidative enzyme capacity | High | Intermediate-high | Low |
| Z-line width | Intermediate | Wide | Narrow |
| Alkaline ATPase activity | Low | High | High |
| Acidic ATPase activity | High | Medium-high | Low |
Slow oxidative (type I) fibers contract relatively slowly and use aerobic respiration to produce ATP. Fast oxidative (type IIA) fibers have fast contractions and primarily use aerobic respiration, but because they may switch to anaerobic respiration (glycolysis), can fatigue more quickly than slow oxidative fibers. Fast glycolytic (type IIX) fibers have fast contractions and primarily use anaerobic glycolysis. The FG fibers fatigue more quickly than the others. Most skeletal muscles in a human contain(s) all three types, although in varying proportions.[35]
Traditionally, fibers were categorized depending on their varying color, which is a reflection ofmyoglobin content. Type I fibers appear red due to the high levels of myoglobin. Red muscle fibers tend to have more mitochondria and greater local capillary density. These fibers are more suited for endurance and are slow to fatigue because they useoxidative metabolism to generate ATP (adenosine triphosphate). Less oxidative Type II fibers are white due to relatively low myoglobin and a reliance on glycolytic enzymes.
Fibers can also be classified on their twitch capabilities, into fast and slow twitch. These traits largely, but not completely, overlap the classifications based on color, ATPase, or MHC (myosin heavy chain).
Some authors define a fast twitch fiber as one in which the myosin can split ATP very quickly. These mainly include the ATPase type II and MHC type II fibers. However, fast twitch fibers also demonstrate a higher capability for electrochemical transmission of action potentials and a rapid level of calcium release and uptake by the sarcoplasmic reticulum. The fast twitch fibers rely on a well-developed,anaerobic, short term, glycolytic system for energy transfer and can contract and develop tension at 2–3 times the rate of slow twitch fibers. Fast twitch muscles are much better at generating short bursts of strength or speed than slow muscles, and so fatigue more quickly.[36]
The slow twitch fibers generate energy for ATP re-synthesis by means of a long term system ofaerobic energy transfer. These mainly include the ATPase type I and MHC type I fibers. They tend to have a low activity level of ATPase, a slower speed of contraction with a less well developed glycolytic capacity.[36] Fibers that become slow-twitch develop greater numbers of mitochondria and capillaries making them better for prolonged work.[37]
Individual muscles tend to be a mixture of various fiber types, but their proportions vary depending on the actions of that muscle. For instance, in humans, thequadriceps muscles contain ~52% type I fibers, while thesoleus is ~80% type I.[38] The orbicularis oculi muscle of the eye is only ~15% type I.[38]Motor units within the muscle, however, have minimal variation between the fibers of that unit. It is this fact that makes the size principal ofmotor unit recruitment viable.
The total number of skeletal muscle fibers has traditionally been thought not to change.It is believed there are no sex or age differences in fiber distribution; however, proportions of fiber types vary considerably from muscle to muscle and person to person.[citation needed] Among different species there is much variation in the proportions of muscle fiber types.[39]
Sedentary men and women (as well as young children) have 45% type II and 55% type I fibers.[citation needed]People at the higher end of any sport tend to demonstrate patterns of fiber distribution e.g. endurance athletes show a higher level of type I fibers.Sprint athletes, on the other hand, require large numbers of type IIX fibers.Middle-distance event athletes show approximately equal distribution of the two types. This is also often the case for power athletes such as throwers and jumpers.It has been suggested that various types of exercise can induce changes in the fibers of a skeletal muscle.[40]
It is thought that by performing endurance type events for a sustained period of time, some of the type IIX fibers transform into type IIA fibers. However, there is no consensus on the subject.[citation needed]It may well be that the type IIX fibers show enhancements of the oxidative capacity after high intensity endurance training which brings them to a level at which they are able to perform oxidative metabolism as effectively as slow twitch fibers of untrained subjects. This would be brought about by an increase in mitochondrial size and number and the associated related changes, not a change in fiber type.
There are numerous methods employed for fiber-typing, and confusion between the methods is common among non-experts. Two commonly confused methods arehistochemical staining formyosin ATPase activity andimmunohistochemical staining for myosin heavy chain (MHC) type. Myosin ATPase activity is commonly—and correctly—referred to as simply "fiber type", and results from the direct assaying of ATPase activity under various conditions (e.g.pH).[34]Myosin heavy chain staining is most accurately referred to as "MHC fiber type", e.g. "MHC IIa fibers", and results from determination of different MHCisoforms.[34] These methods are closely related physiologically, as the MHC type is the primary determinant of ATPase activity. However, neither of these typing methods is directly metabolic in nature; they do not directly address oxidative or glycolytic capacity of the fiber.
When "type I" or "type II" fibers are referred to generically, this most accurately refers to the sum of numerical fiber types (I vs. II) as assessed by myosin ATPase activity staining (e.g. "type II" fibers refers to type IIA + type IIAX + type IIXA ... etc.).
Below is a table showing the relationship between these two methods, limited to fiber types found in humans. Subtype capitalization is used in fiber typing vs. MHC typing, and some ATPase types actually contain multiple MHC types. Also, asubtype B or b is not expressed in humans by either method.[41] Early researchers believed humans to express a MHC IIb, which led to the ATPase classification of IIB. However, later research showed that the human MHC IIb was in fact IIx,[41] indicating that the IIB is better named IIX. IIb is expressed in other mammals, so is still accurately seen (along with IIB) in the literature. Non human fiber types include true IIb fibers, IIc, IId, etc.
| ATPase type | MHC heavy chain(s) |
|---|---|
| Type I | MHC Iβ |
| Type IC | MHC Iβ > MHC IIa |
| Type IIC | MHC IIa > MHC Iβ |
| Type IIA | MHC IIa |
| Type IIAX | MHC IIa > MHC IIx |
| Type IIXA | MHC IIx > MHC IIa |
| Type IIX | MHC IIx |
Further fiber typing methods are less formally delineated, and exist on more of a spectrum. They tend to be focused more on metabolic and functional capacities (i.e., oxidative vs.glycolytic, fast vs. slow contraction time). As noted above, fiber typing by ATPase or MHC does not directly measure or dictate these parameters. However, many of the various methods are mechanistically linked, while others are correlatedin vivo.[44][45] For instance, ATPase fiber type is related to contraction speed, because high ATPase activity allows fastercrossbridge cycling.[34] While ATPase activity is only one component of contraction speed, Type I fibers are "slow", in part, because they have low speeds of ATPase activity in comparison to Type II fibers. However, measuring contraction speed is not the same as ATPase fiber typing.
Almost all multicellular animals depend on muscles to move.[46] Generally, muscular systems of most multicellular animals comprise both slow-twitch and fast-twitch muscle fibers, though the proportions of each fiber type can vary across organisms and environments. The ability to shift their phenotypic fiber type proportions through training and responding to the environment has served organisms well when placed in changing environments either requiring short explosive movements (higher fast twitch proportion) or long duration of movement (higher slow twitch proportion) to survive.[47] Bodybuilding has shown that changes in muscle mass and force production can change in a matter of months.[48] Some examples of this variation are described below.[49]
American lobster,Homarus americanus, has three fiber types including fast twitch fibers, slow-twitch and slow-tonic fibers.[50] Slow-tonic is a slow twitch-fiber that can sustain longer contractions (tonic).[51][52] In lobsters, muscles in different body parts vary in the muscle fiber type proportions based on the purpose of the muscle group.[50]
In the earlydevelopment of vertebrate embryos, growth and formation of muscle happens in successive waves or phases ofmyogenesis. The myosin heavy chainisotype is a major determinant of the specific fiber type. Inzebrafish embryos, the first muscle fibers to form are the slow twitch fibers. These cells will undergo migration from their original location to form a monolayer of slow twitch muscle fibers. These muscle fibers undergo furtherdifferentiation as the embryo matures.[53]
In larger animals, different muscle groups will increasingly require different fiber type proportions within muscle for different purposes.Turtles, such asTrachemys scripta elegans, have complementary muscles within the neck that show a potential inverse trend of fiber type percentages (one muscle has high percentage of fast twitch, while the complementary muscle will have a higher percentage of slow twitch fibers). The complementary muscles of turtles had similar percentages of fiber types.[51]
Chimpanzee muscles are composed of 67% fast-twitch fibers and have a maximum dynamic force and power output 1.35 times higher than human muscles of similar size. Among mammals, there is a predominance of type II fibers utilizing glycolytic metabolism. Because of the discrepancy in fast twitch fibers compared to humans, chimpanzees outperform humans in power related tests. Humans, however, will do better at exercise in aerobic range requiring large metabolic costs such as walking (bipedalism).[54]
Across species, certain gene sequences have been preserved, but do not always have the same functional purpose. Within the zebrafish embryo, thePrdm1 gene down-regulates the formation of new slow twitch fibers through direct and indirect mechanisms such asSox6 (indirect). In mice, thePrdm1 gene is present but does not control slow muscle genes in mice throughSox6.[55]
In addition to having a genetic basis, the composition of muscle fiber types is flexible and can vary with a number of different environmental factors. This plasticity can, arguably, be the strongest evolutionary advantage among organisms with muscle.
In fish, different fiber types are expressed at different water temperatures.[53] Cold temperatures require more efficient metabolism within muscle and fatigue resistance is important. While in more tropical environments, fast powerful movements (from higher fast-twitch proportions) may prove more beneficial in the long run.[56]
In rodents such as rats, the transitory nature of their muscle is highly prevalent. They have high percentage of hybrid muscle fibers and have up to 60% in fast-to-slow transforming muscle.[48]
Environmental influences such as diet, exercise and lifestyle types have a pivotal role in proportions of fiber type in humans. Aerobic exercise will shift the proportions towards slow twitch fibers, while explosive powerlifting and sprinting will transition fibers towards fast twitch.[47] In animals, "exercise training" will look more like the need for long durations of movement or short explosive movements to escape predators or catch prey.[57]
Skeletal muscle exhibits a distinctive banding pattern when viewed under the microscope due to the arrangement of two contractile proteinsmyosin, andactin – that are two of themyofilaments in themyofibrils. The myosin forms the thick filaments, and actin forms the thin filaments, and are arranged in repeating units calledsarcomeres. The interaction of both proteins results in muscle contraction.
The sarcomere is attached to other organelles such as the mitochondria byintermediate filaments in the cytoskeleton. Thecostamere attaches the sarcomere to the sarcolemma.[5]
Every single organelle and macromolecule of a muscle fiber is arranged to ensure that it meets desired functions. Thecell membrane is called the sarcolemma with the cytoplasm known as thesarcoplasm. In the sarcoplasm are the myofibrils. The myofibrils are long protein bundles about one micrometer in diameter. Pressed against the inside of the sarcolemma are the unusual flattened myonuclei. Between the myofibrils are themitochondria.
While the muscle fiber does not have smooth endoplasmic cisternae, it containssarcoplasmic reticulum. The sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of thecalcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known asterminal cisternae. These cross the muscle fiber from one side to the other. In between two terminal cisternae is a tubular infolding called a transverse tubule (T tubule).T tubules are the pathways for action potentials to signal the sarcoplasmic reticulum to release calcium, causing a muscle contraction. Together, two terminal cisternae and a transverse tubule form atriad.[58]
All muscles are derived fromparaxial mesoderm. Duringembryonic development in the process ofsomitogenesis the paraxial mesoderm is divided along theembryo's length to formsomites, corresponding to thesegmentation of the body most obviously seen in thevertebral column.[59] Each somite has three divisions,sclerotome (which formsvertebrae),dermatome (which forms skin), andmyotome (which forms muscle). The myotome is divided into two sections, the epimere and hypomere, which formepaxial and hypaxial muscles, respectively. The only epaxial muscles in humans are theerector spinae and small vertebral muscles, and are innervated by the dorsal rami of thespinal nerves. All other muscles, including those of the limbs are hypaxial, and innervated by theventral rami of the spinal nerves.[59]
During development,myoblasts (muscle progenitor cells) either remain in the somite to form muscles associated with the vertebral column or migrate out into the body to form all other muscles. Myoblast migration is preceded by the formation ofconnective tissue frameworks, usually formed from the somaticlateral plate mesoderm. Myoblasts follow chemical signals to the appropriate locations, where they fuse into elongated multinucleated skeletal muscle cells.[59]
Between the tenth and the eighteenth weeks of gestation, all muscle cells have fast myosin heavy chains; two myotube types become distinguished in the developingfetus – both expressing fast chains but one expressing fast and slow chains. Between 10 and 40 per cent of the fibers express the slow myosin chain.[60]
Fiber types are established during embryonic development and are remodelled later in the adult by neural and hormonal influences.[39] The population of satellite cells present underneath the basal lamina is necessary for the postnatal development of muscle cells.[61]
The primary function of muscle iscontraction.[3] Following contraction, skeletal muscle functions as anendocrine organ by secretingmyokines – a wide range ofcytokines and otherpeptides that act as signalling molecules.[62] Myokines in turn are believed to mediate the health benefits ofexercise.[63] Myokines are secreted into the bloodstream after muscle contraction.Interleukin 6 (IL-6) is the most studied myokine, other muscle contraction-induced myokines includeBDNF,FGF21, andSPARC.[64]
Muscle also functions to produce body heat. Muscle contraction is responsible for producing 85% of the body's heat.[65] This heat produced is as a by-product of muscular activity, and is mostly wasted. As ahomeostatic response to extreme cold, muscles are signaled to trigger contractions ofshivering in order to generate heat.[66]
Contraction is achieved by the muscle's structural unit, the muscle fiber, and by its functional unit, themotor unit.[4] Muscle fibers areexcitable cells stimulated bymotor neurons. The motor unit consists of a motor neuron and the many fibers that it makes contact with. A single muscle is stimulated by many motor units. Muscle fibers aresubject todepolarization by the neurotransmitteracetylcholine, released by the motor neurons at theneuromuscular junctions.[67]
In addition to theactin andmyosinmyofilaments in themyofibrils that make up the contractilesarcomeres, there are two other important regulatory proteins –troponin andtropomyosin, that make muscle contraction possible. These proteins are associated with actin and cooperate to prevent its interaction with myosin. Once a cell is sufficiently stimulated, the cell'ssarcoplasmic reticulumreleases ionic calcium (Ca2+), which then interacts with the regulatory protein troponin. Calcium-bound troponin undergoes a conformational change that leads to the movement of tropomyosin, subsequently exposing the myosin-binding sites on actin. This allows for myosin and actin ATP-dependentcross-bridge cycling and shortening of the muscle.
Excitation contraction coupling is the process by which amuscular action potential in the muscle fiber causes themyofibrils to contract. This process relies on a direct coupling between thesarcoplasmic reticulum calcium release channelRYR1 (ryanodine receptor 1), andvoltage-gated L-type calcium channels (identified as dihydropyridine receptors, DHPRs). DHPRs are located on the sarcolemma (which includes the surface sarcolemma and thetransverse tubules), while the RyRs reside across the SR membrane. The close apposition of a transverse tubule and two SR regions containing RyRs is described as a triad and is predominantly where excitation–contraction coupling takes place. Excitation–contraction coupling occurs when depolarization of skeletal muscle cell results in a muscle action potential, which spreads across the cell surface and into the muscle fiber's network ofT-tubules, thereby depolarizing the inner portion of the muscle fiber. Depolarization of the inner portions activates dihydropyridine receptors in the terminal cisternae, which are close to ryanodine receptors in the adjacentsarcoplasmic reticulum. The activated dihydropyridine receptors physically interact with ryanodine receptors to activate them via foot processes (involving conformational changes that allosterically activates the ryanodine receptors). As the ryanodine receptors open,Ca2+
is released from the sarcoplasmic reticulum into the local junctional space and diffuses into the bulk cytoplasm to cause acalcium spark. The sarcoplasmic reticulum has a largecalcium buffering capacity partially due to acalcium-binding protein calledcalsequestrin. The near synchronous activation of thousands ofcalcium sparks by the action potential causes a cell-wide increase in calcium giving rise to the upstroke of thecalcium transient. TheCa2+
released into the cytosol binds toTroponin C by theactin filaments, to allow crossbridge cycling, producing force and, in some situations, motion. Thesarco/endoplasmic reticulum calcium-ATPase (SERCA) actively pumpsCa2+
back into the sarcoplasmic reticulum. AsCa2+
declines back to resting levels, the force declines and relaxation occurs.[68]
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Theefferent leg of theperipheral nervous system is responsible for conveying commands to the muscles and glands, and is ultimately responsible for voluntary movement.Nerves move muscles in response tovoluntary andautonomic (involuntary) signals from thebrain. Deep muscles, superficial muscles,muscles of the face and internal muscles all correspond with dedicated regions in the primary motor cortex of thebrain, directly anterior to the central sulcus that divides the frontal and parietal lobes.
In addition, muscles react toreflexive nerve stimuli that do not always send signals all the way to the brain. In this case, the signal from the afferent fiber does not reach the brain, but produces the reflexive movement by direct connections with the efferent nerves in thespine. However, the majority of muscle activity is volitional, and the result of complex interactions between various areas of the brain.
Nerves that control skeletal muscles inmammals correspond with neuron groups along theprimary motor cortex of the brain'scerebral cortex. Commands are routed through thebasal ganglia and are modified by input from thecerebellum before being relayed through thepyramidal tract to thespinal cord and from there to themotor end plate at the muscles. Along the way, feedback, such as that of theextrapyramidal system contribute signals to influencemuscle tone and response.
Deeper muscles such as those involved inposture often are controlled from nuclei in thebrain stem and basal ganglia.
In skeletal muscles,muscle spindles convey information about the degree of muscle length and stretch to the central nervous system to assist in maintaining posture and joint position. Thesense of where our bodies are in space is calledproprioception, the perception of body awareness, the "unconscious" awareness of where the various regions of the body are located at any one time. Several areas in the brain coordinate movement and position with the feedback information gained from proprioception. The cerebellum andred nucleus in particular continuously sample position against movement and make minor corrections to assure smooth motion.[citation needed]
Muscular activity accounts for much of the body'senergy consumption. All muscle cells produceadenosine triphosphate (ATP) molecules which are used to power the movement of themyosin heads. Muscles have a short-term store of energy in the form ofcreatine phosphate which is generated from ATP and can regenerate ATP when needed withcreatine kinase. Muscles also keep a storage form of glucose in the form ofglycogen. Glycogen can be rapidly converted toglucose when energy is required for sustained, powerful contractions. Within the voluntary skeletal muscles, the glucose molecule can be metabolized anaerobically in a process called glycolysis which produces two ATP and twolactic acid molecules in the process (in aerobic conditions, lactate is not formed; insteadpyruvate is formed and transmitted through thecitric acid cycle). Muscle cells also contain globules of fat, which are used for energy duringaerobic exercise. The aerobic energy systems take longer to produce the ATP and reach peak efficiency, and requires many more biochemical steps, but produces significantly more ATP than anaerobic glycolysis. Cardiac muscle on the other hand, can readily consume any of the three macronutrients (protein, glucose and fat) aerobically without a 'warm up' period and always extracts the maximum ATP yield from any molecule involved. The heart, liver and red blood cells will also consume lactic acid produced and excreted by skeletal muscles during exercise.
Skeletal muscle uses more calories than other organs.[69]At rest it consumes 54.4 kJ/kg (13.0 kcal/kg) per day. This is larger thanadipose tissue (fat) at 18.8 kJ/kg (4.5 kcal/kg), and bone at 9.6 kJ/kg (2.3 kcal/kg).[70]
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Theefficiency of human muscle has been measured (in the context ofrowing andcycling) at 18% to 26%. The efficiency is defined as the ratio ofmechanical work output to the totalmetabolic cost, as can be calculated from oxygen consumption. This low efficiency is the result of about 40% efficiency of generatingATP fromfood energy, losses in converting energy from ATP into mechanical work inside the muscle, and mechanical losses inside the body. The latter two losses are dependent on the type of exercise and the type of muscle fibers being used (fast-twitch or slow-twitch). For an overall efficiency of 20 percent, one watt of mechanical power is equivalent to 4.3 kcal per hour. For example, one manufacturer of rowing equipment calibrates itsrowing ergometer to count burned calories as equal to four times the actual mechanical work, plus 300 kcal per hour, this amounts to about 20 percent efficiency at 250 watts of mechanical output. The mechanical energy output of a cyclic contraction can depend upon many factors, including activation timing, muscle strain trajectory, and rates of force rise & decay. These can be synthesized experimentally usingwork loop analysis.
| Grade 0 | No contraction |
| Grade 1 | Trace of contraction, but no movement at the joint |
| Grade 2 | Movement at the joint with gravity eliminated |
| Grade 3 | Movement against gravity, but not against added resistance |
| Grade 4 | Movement against external resistance, but less than normal |
| Grade 5 | Normal strength |
Muscle strength is a result of three overlapping factors:physiological strength (muscle size, cross sectional area, available crossbridging, responses to training),neurological strength (how strong or weak is the signal that tells the muscle to contract), andmechanical strength (muscle's force angle on the lever, moment arm length, joint capabilities).[citation needed]
Vertebrate muscle typically produces approximately 25–33 N (5.6–7.4 lbf) of force per square centimeter of muscle cross-sectional area when isometric and at optimal length.[71] Someinvertebrate muscles, such as in crab claws, have much longersarcomeres than vertebrates, resulting in many more sites for actin and myosin to bind and thus much greater force per square centimeter at the cost of much slower speed. The force generated by a contraction can be measured non-invasively using eithermechanomyography orphonomyography, be measuredin vivo using tendon strain (if a prominent tendon is present), or be measured directly using more invasive methods.
The strength of any given muscle, in terms of force exerted on the skeleton, depends uponlength, shortening speed, cross sectional area,pennation,sarcomere length,myosin isoforms, and neural activation ofmotor units. Significant reductions in muscle strength can indicate underlying pathology, with the chart at right used as a guide.
Themaximum holding time for a contracted muscle depends on its supply of energy and is stated byRohmert's law toexponentially decay from the beginning of exertion.
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Since three factors affect muscular strength simultaneously and muscles never work individually, it is misleading to compare strength in individual muscles, and state that one is the "strongest". But below are several muscles whose strength is noteworthy for different reasons.
Muscle force is proportional tophysiological cross-sectional area (PCSA), and muscle velocity is proportional to muscle fiber length.[72] The torque around a joint, however, is determined by a number of biomechanical parameters, including the distance between muscle insertions and pivot points, muscle size andarchitectural gear ratio. Muscles are normally arranged in opposition so that when one group of muscles contracts, another group relaxes or lengthens.[73] Antagonism in the transmission of nerve impulses to the muscles means that it is impossible to fully stimulate the contraction of twoantagonistic muscles at any one time. During ballistic motions such as throwing, the antagonist muscles act to 'brake' theagonist muscles throughout the contraction, particularly at the end of the motion. In the example of throwing, the chest and front of the shoulder (anterior deltoid) contract to pull the arm forward, while the muscles in the back and rear of the shoulder (posterior deltoid) also contract and undergo eccentric contraction to slow the motion down to avoid injury. Part of the training process is learning to relax the antagonist muscles to increase the force input of the chest and anterior shoulder.
Contracting muscles produce vibration and sound.[74] Slow twitch fibers produce 10 to 30 contractions per second (10 to 30 Hz). Fast twitch fibers produce 30 to 70 contractions per second (30 to 70 Hz).[75] The vibration can be witnessed and felt by highly tensing one's muscles, as when making a firm fist. The sound can be heard by pressing a highly tensed muscle against the ear, again a firm fist is a good example. The sound is usually described as a rumbling sound. Some individuals can voluntarily produce this rumbling sound by contracting thetensor tympani muscle of the middle ear. The rumbling sound can also be heard when the neck or jaw muscles are highly tensed.[citation needed]
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Skeletal muscle fiber-type phenotype in adult animals is regulated by several independent signaling pathways. These include pathways involved with theRas/mitogen-activated protein kinase (MAPK) pathway, calcineurin, calcium/calmodulin-dependent protein kinase IV, and the peroxisome proliferator γ coactivator 1 (PGC-1). TheRas/MAPK signaling pathway links the motor neurons and signaling systems, coupling excitation and transcription regulation to promote the nerve-dependent induction of the slow program in regenerating muscle.Calcineurin, a Ca2+/calmodulin-activatedphosphatase implicated in nerve activity-dependent fiber-type specification in skeletal muscle, directly controls the phosphorylation state of the transcription factorNFAT, allowing for its translocation to the nucleus and leading to the activation of slow-type muscle proteins in cooperation with myocyte enhancer factor 2 (MEF2) proteins and other regulatory proteins.Ca2+/calmodulin-dependent protein kinase activity is also upregulated by slow motor neuron activity, possibly because it amplifies the slow-type calcineurin-generated responses by promoting MEF2transactivator functions and enhancing oxidative capacity through stimulation ofmitochondrial biogenesis.
Contraction-induced changes in intracellular calcium or reactive oxygen species provide signals to diverse pathways that include the MAPKs, calcineurin and calcium/calmodulin-dependent protein kinase IV to activate transcription factors that regulate gene expression and enzyme activity in skeletal muscle.
PGC1-α (PPARGC1A), a transcriptional coactivator of nuclear receptors important to the regulation of a number of mitochondrial genes involved in oxidative metabolism, directly interacts with MEF2 to synergistically activate selective slow twitch (ST) muscle genes and also serves as a target for calcineurin signaling. A peroxisome proliferator-activated receptor δ (PPARδ)-mediated transcriptional pathway is involved in the regulation of the skeletal muscle fiber phenotype. Mice that harbor an activated form of PPARδ display an "endurance" phenotype, with a coordinated increase in oxidative enzymes andmitochondrial biogenesis and an increased proportion of ST fibers. Thus—through functional genomics—calcineurin, calmodulin-dependent kinase, PGC-1α, and activated PPARδ form the basis of a signaling network that controls skeletal muscle fiber-type transformation and metabolic profiles that protect against insulin resistance and obesity.
The transition from aerobic to anaerobic metabolism during intense work requires that several systems are rapidly activated to ensure a constant supply of ATP for the working muscles. These include a switch from fat-based to carbohydrate-based fuels, a redistribution of blood flow from nonworking to exercising muscles, and the removal of several of the by-products of anaerobic metabolism, such as carbon dioxide and lactic acid. Some of these responses are governed by transcriptional control of the fast twitch (FT) glycolytic phenotype. For example, skeletal muscle reprogramming from an ST glycolytic phenotype to an FT glycolytic phenotype involves the Six1/Eya1 complex, composed of members of the Six protein family. Moreover, the hypoxia-inducible factor 1-α (HIF1A) has been identified as a master regulator for the expression of genes involved in essential hypoxic responses that maintain ATP levels in cells.Ablation of HIF-1α in skeletal muscle was associated with an increase in the activity of rate-limiting enzymes of the mitochondria, indicating that the citric acid cycle and increased fatty acid oxidation may be compensating for decreased flow through the glycolytic pathway in these animals. However, hypoxia-mediated HIF-1α responses are also linked to the regulation of mitochondrial dysfunction through the formation of excessive reactive oxygen species in mitochondria.
Other pathways also influence adult muscle character. For example, physical force inside a muscle fiber may release the transcription factorserum response factor from the structural protein titin, leading to altered muscle growth.
Physical exercise is often recommended as a means of improvingmotor skills,fitness, muscle and bone strength, and joint function. Exercise has several effects upon muscles,connective tissue, bone, and the nerves that stimulate the muscles. One such effect ismuscle hypertrophy, an increase in size of muscle due to an increase in the number of muscle fibers or cross-sectional area of myofibrils.[76] Muscle changes depend on the type of exercise used.
Generally, there are two types of exercise regimes, aerobic and anaerobic.Aerobic exercise (e.g. marathons) involves activities of low intensity but long duration, during which the muscles used are below their maximal contraction strength. Aerobic activities rely on aerobic respiration (i.e. citric acid cycle and electron transport chain) for metabolic energy by consuming fat, protein, carbohydrates, and oxygen. Muscles involved in aerobic exercises contain a higher percentage of Type I (or slow-twitch) muscle fibers, which primarily contain mitochondrial and oxidation enzymes associated with aerobic respiration.[77][78] On the contrary,anaerobic exercise is associated with activities of high intensity but short duration, such as sprinting orweight lifting. The anaerobic activities predominately use Type II, fast-twitch, muscle fibers.[79] Type II muscle fibers rely on Gluconeogenesis for energy during anaerobic exercise.[80] During anaerobic exercise, type II fibers consume little oxygen, protein and fat, produce large amounts of lactic acid and are fatigable. Many exercises are partially aerobic and anaerobic; for example,soccer androck climbing.
The presence oflactic acid has an inhibitory effect on ATP generation within the muscle. It can even stop ATP production if the intracellular concentration becomes too high. However, endurance training mitigates the buildup of lactic acid through increased capillarization and myoglobin.[81] This increases the ability to remove waste products, like lactic acid, out of the muscles in order to not impair muscle function. Once moved out of muscles, lactic acid can be used by other muscles or body tissues as a source of energy, or transported to the liver where it is converted back topyruvate. In addition to increasing the level of lactic acid, strenuous exercise results in the loss of potassium ions in muscle. This may facilitate the recovery of muscle function by protecting against fatigue.[82]
Delayed onset muscle soreness is pain or discomfort that may be felt one to three days after exercising and generally subsides two to three days later. Once thought to be caused by lactic acid build-up, a more recent theory is that it is caused by tiny tears in the muscle fibers caused byeccentric contraction, or unaccustomed training levels. Since lactic acid disperses fairly rapidly, it could not explain pain experienced days after exercise.[83]
Diseases of skeletal muscle are termedmyopathies, while diseases of nerves are calledneuropathies. Both can affect muscle function or cause muscle pain, and fall under the umbrella ofneuromuscular disease. The cause of many myopathies is attributed to mutations in the various associated muscle proteins.[5][84] Someinflammatory myopathies includepolymyositis andinclusion body myositis
Neuromuscular diseases affect the muscles and their nervous control. In general, problems with nervous control can causespasticity orparalysis, depending on the location and nature of the problem. A number ofmovement disorders are caused byneurological disorders such asParkinson's disease andHuntington's disease where there is central nervous system dysfunction.[85]
Symptoms of muscle diseases may includeweakness, spasticity,myoclonus andmyalgia. Diagnostic procedures that may reveal muscular disorders include testingcreatine kinase levels in the blood andelectromyography (measuring electrical activity in muscles). In some cases,muscle biopsy may be done to identify amyopathy, as well asgenetic testing to identifyDNA abnormalities associated with specific myopathies anddystrophies.
A non-invasiveelastography technique that measures muscle noise is undergoing experimentation to provide a way of monitoring neuromuscular disease. The sound produced by a muscle comes from the shortening ofactomyosinfilaments along the axis of the muscle. Duringcontraction, the muscle shortens along its length and expands across its width, producingvibrations at the surface.[86]
Independent of strength and performance measures, muscles can be induced to grow larger by a number of factors, including hormone signaling, developmental factors,strength training, and disease. Contrary to popular belief, the number of muscle fibres cannot be increased throughexercise. Instead, muscles grow larger through a combination of muscle cell growth as new protein filaments are added along with additional mass provided by undifferentiated satellite cells alongside the existing muscle cells.[87]
Biological factors such as age and hormone levels can affect muscle hypertrophy. Duringpuberty in males, hypertrophy occurs at an accelerated rate as the levels of growth-stimulatinghormones produced by the body increase. Natural hypertrophy normally stops at full growth in the late teens. Astestosterone is one of the body's major growth hormones, on average, men find hypertrophy much easier to achieve than women. Taking additional testosterone or otheranabolic steroids will increase muscular hypertrophy.
Muscular, spinal and neural factors all affect muscle building. Sometimes a person may notice an increase in strength in a given muscle even though only its opposite has been subject to exercise, such as when a bodybuilder finds her left biceps stronger after completing a regimen focusing only on the right biceps. This phenomenon is calledcross education.[citation needed]
Every day between one and two percent of muscle is broken down and rebuilt.Inactivity,malnutrition,disease, andaging can increase the breakdown leading tomuscle atrophy orsarcopenia. Sarcopenia is commonly an age-related process that can causefrailty and its consequences.[88] A decrease in muscle mass may be accompanied by a smaller number and size of the muscle cells as well as lower protein content.[89]
Human spaceflight, involving prolonged periods of immobilization and weightlessness is known to result in muscle weakening and atrophy resulting in a loss of as much as 30% of mass in some muscles.[90][91] Such consequences are also noted in some mammals followinghibernation.[92]
Many diseases and conditions includingcancer,AIDS, andheart failure can cause muscle loss known ascachexia.[93]
Myopathies have been modeled with cell culture systems of muscle from healthy or diseased tissuebiopsies. Another source of skeletal muscle and progenitors is provided by thedirected differentiation ofpluripotent stem cells.[94]
Research on skeletal muscle properties uses many techniques.Electrical muscle stimulation is used to determine force and contraction speed at different frequencies related to fiber-type composition and mix within an individual muscle group.In vitro muscle testing is used for more complete characterization of muscle properties.
The electrical activity associated with muscle contraction is measured viaelectromyography (EMG). Skeletal muscle has two physiological responses: relaxation and contraction. The mechanisms for which these responses occur generate electrical activity measured by EMG. Specifically, EMG can measure the action potential of a skeletal muscle, which occurs from thehyperpolarization of the motoraxons from nerve impulses sent to the muscle. EMG is used in research for determining if the skeletal muscle of interest is being activated, the amount offorce generated, and an indicator ofmuscle fatigue.[95] The two types of EMG are intra-muscular EMG and the most common, surface EMG. The EMG signals are much greater when a skeletal muscle is contracting versus relaxing. However, for smaller and deeper skeletal muscles the EMG signals are reduced and therefore are viewed as a less valued technique for measuring the activation.[96] In research using EMG, amaximal voluntary contraction (MVC) is commonly performed on the skeletal muscle of interest, to have reference data for the rest of the EMG recordings during the main experimental testing for that same skeletal muscle.[97]
Research into the development ofartificial muscles includes the use ofelectroactive polymers.
Nuclei present in skeletal muscle are about 50% myocyte nuclei and 50% mononuclear cell nuclei.[13] Mononuclear cells found in skeletal muscle tissue samples from mice and humans[15][99][98] can be identified bymessenger RNA transcription of cell type markers. Cameron et al.[98] identified nine cell types. They includeendothelial cells that line capillaries (45% of cells), fibro-adipogenic progenitors (FAPs)(20%),[100]pericytes (14%) and endothelial-like pericytes (4%). Another 9% of mononuclear cells aremuscle stem cells, adjacent to muscle fiber cells. Types oflymphoid cells (such as B-cells and T-cells) (3%) and myeloid cells such asmacrophages (2%) made up most of the remaining mononuclear cells of skeletal muscle.[98] In addition, Cameron et al.[98] also identified two types of myocyte cells, Type I and Type II. Each of the different types of cells in skeletal muscle was found to express different sets of genes. The median number of genes expressed in each of the nine different cell types was 1,331 genes. When a biopsy is taken from a thigh muscle, however, the biopsy contains all the different cell types. Mixed together, in a biopsy of human thigh skeletal muscle, there are 13,026 to 13,108 genes with detected expression.[101][102]
As pointed out in the Introduction to this article, under different physiological conditions, subsets of 654 different proteins as well as lipids, amino acids, metabolites and small RNAs occur in thesecretome of skeletal muscles.[12] As described in the Wikipedia article "List of human endocrine organs and actions", skeletal muscle is identified as anendocrine organ due to its secretion ofcytokines and other peptides produced by skeletal muscle as signaling molecules. Iizuka et al.,[9] indicated that skeletal muscle is an endocrine organ because it "synthesizes and secretes multiple factors, and these muscle derived-factors exert beneficial effects on peripheral and remote organs." The altered secretomes afterendurance training orresistance training as well as the secretome of sedentary muscle appear to have many effects on distant tissues.
A study in Canada tested the effect of muscle mass on mental functions during aging. An expectation of the study was that the endocrine components of the secretome specific to skeletal muscle could protect cognitive functions. The skeletal muscle mass of arms and legs of 8,279 Canadians over the age of 65 and in average health was measured at baseline and after three years.[103] Of these individuals, 1,605 participants (19.4%) were considered to have a low skeletal muscle mass at baseline, with less than 7.30 kg/m2 for males, and less than 5.42 kg/m2 for females (levels defined assarcopenia in Canada).
Executive mental function, memory and psychomotor speed were each measured at baseline and after three years. Executive mental function was measured with standard tests, including the ability to say the sequence 1-A, 2-B, 3-C…, to name a number of animals in one minute, and with theStroop test.[103] The study found that those individuals with lower skeletal muscle mass at the start of the study declined in their executive mental function considerably more sharply than those with higher muscle mass. Memory, as well as psychomotor speed, on the other hand, did not correlate with skeletal muscle mass.[103] Thus, larger muscle mass, with a concomitantly larger secretome, appeared to have the endocrine function of protecting the executive mental function of individuals over the age of 65.
Paluch et al.[104] compared the average number of stepswalked per day to the risk ofmortality, both for adults over 60 years old and for adults under 60 years old. The study was a meta-analysis of 15 studies, which, combined, evaluated 47,471 adults over a period of 7 years. Individuals were divided into approximately equal quartiles. The lowest quartile averaged 3,553 steps/day, the second quartile 5,801 steps/day, the third quartile 7,842 steps/day and the fourth quartile 10,901 steps/day. The briskness of walking, adjusted for the volume of walking, did not affect mortality. However, the number of steps/day was clearly related to mortality. When risk of mortality for those over 60 years old was set at 1.0 for the lowest quartile of steps/day, the relative risk of mortality for the second, third and fourth quartiles were 0.56, 0.45, and 0.35, respectively. For those under 60 years of age, the results were less pronounced. For those under 60 years of age, with the first quartile risk of mortality set at 1.0, the second, third and fourth quartile relative risks of mortality were 0.57, 0.42 and 0.53, respectively. Thus, use of skeletal muscles in walking has a large effect, especially among older individuals, on mortality.
Williams et al.[102] obtained biopsies ofa thigh skeletal muscle (vastus lateralis muscle) of eight 23-year old, originally sedentary, Caucasian males. Biopsies were taken both before and after a six-week long endurance exercise training program. The exercise consisted of riding a stationary bicycle for one hour, five days a week for six weeks.
Of the 13,108 genes with detected expression in the muscle biopsies, 641 genes were upregulated after endurance training and 176 genes were downregulated. Of the 817 total altered genes, 531 were identified as being in the secretome by either or both ofUniprot orExocarta, or else by studies investigating the secretome of muscle cells. Because many of the exercise-regulated genes are identified as secreted, this indicates that much of the effect of exercise has an endocrine rather than metabolic function.[102] The main pathways found to be affected by secreted exercise-regulated proteins were related tocardiac,cognitive,kidney andplatelet functions.
Between 2012 and 2019, at least 25 reports indicated a major role ofepigenetic mechanisms in skeletal muscle responses to exercise.[105] Epigenetic alterations often occur byadding methyl groups to cytosines in the DNA orremoving methyl groups from the cytosines of DNA, especially atCpG sites. Methylations of cytosines can cause the DNA to be compacted intoheterochromatin, thus inhibiting access of other molecules to the DNA.[106] Epigenetic alterations also often occur through acetylations or deacetylations of thehistone tails withinchromatin. DNA in the nucleus generally consists of segments of 146base pairs of DNA wrapped around eight tightly connectedhistones (and each histone also has a loose tail) in a structure called anucleosome and one segment of DNA is connected to an adjacent DNA segment on a nucleosome bylinker DNA. When histone tails areacetylated, they usually cause loosening of the DNA around the nucleosome, leading to increased accessibility of the DNA.
Gene expression in muscle is largely regulated, as in tissues generally, byregulatory DNA sequences, especiallyenhancers. Enhancers are non-coding sequences in the genome that activate the expression of distant target genes,[107] by looping around and interacting with thepromoters of their target genes[108] (see Figure "Regulation of transcription in mammals"). As reported by Williams et al.,[102] the average distance in the loop between the connected enhancers and promoters of genes is 239,000 nucleotide bases.
Endurance muscle training alters muscle gene expression by epigeneticDNA methylation or de-methylation ofCpG sites within enhancers.[109]
In a study by Lindholm et al.,[109] twenty-three individuals who were about 27 years old and sedentary volunteered to haveendurance training on only one leg during 3 months. The other leg was used as an untrained control leg. The training consisted of one-legged knee extension training for 3 month (45 min, 4 sessions per week). Skeletal muscle biopsies from thevastus lateralis (a thigh muscle) were taken both before training began and 24 hours after the last training session from each of the legs. The endurance-trained leg, compared to the untrained leg, had significantDNA methylation changes at 4,919 sites across the genome. The sites of altered DNA methylation were predominantly inenhancers. Transcriptional analysis, usingRNA sequencing, identified 4,076 differentially expressed genes.
Thetranscriptionally upregulated genes were associated with enhancers that had a significant decrease inDNA methylation, while transcriptionally downregulated genes were associated with enhancers that had increased DNA methylation. Increased methylation was mainly associated with genes involved in structural remodeling of the muscle and glucose metabolism. Enhancers with decreased methylation were associated with genes functioning in inflammatory or immunological processes and in transcriptional regulation.
As indicated above, after exercise,epigenetic alterations toenhancers alter long-termexpression of hundreds of muscle genes.[102] This includes genes producing proteins secreted into the systemic circulation, many of which may act as endocrine messengers.[102] Six sedentary, about 23 years old, Caucasian males providedvastus lateralis (a thigh muscle) biopsies before entering an exercise program (six weeks of 60-minute sessions of riding a stationary cycle, five days per week). Four days after this exercise program was completed, the expression of many genes was persistentlyepigentically altered. The alterations altered acetylations and deacetylations of the histone tails located in the enhancers controlling the genes with altered expression.[102]
Up-regulated genes were associated with epigenetic acetylations added at histone 3 lysine 27 (H3K27ac) of nucleosomes located at theirenhancers. Down-regulated genes were associated with the removal of epigenetic acetylations at H3K27 in nucleosomes located at their enhancers (see Figure "Anucleosome withhistone tails set for transcriptional activation"). Biopsies of the vastus lateralis muscle showed expression of 13,108 genes at baseline before the exercise training program. Four days after the exercise program was completed, biopsies of the same muscles showed altered gene expression, with 641 genes up-regulated and 176 genes down-regulated.[102] Williams et al. identified 599 enhancer-gene interactions, covering 491 enhancers and 268 genes (multiple enhancers were found connected to some genes), where both the enhancer and the connected target gene were coordinately either upregulated or downregulated after exercise training.[102]
This article incorporatestext available under theCC BY 4.0 license.Betts, J Gordon; Desaix, Peter; Johnson, Eddie; Johnson, Jody E; Korol, Oksana; Kruse, Dean; Poe, Brandon; Wise, James; Womble, Mark D; Young, Kelly A (14 May 2023).Anatomy & Physiology. Houston: OpenStax CNX. 10.5 Types of muscle fibres.ISBN 978-1-947172-04-3.
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