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Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the voluntary muscular system and typically are attached by to of a skeleton. The skeletal are much longer than in the other types of muscle tissue, and are also known as muscle fibers. (2025). 9781496347213, Wolters Kluwer. ISBN 9781496347213 The tissue of a skeletal muscle is striated – having a striped appearance due to the arrangement of the .
A skeletal muscle contains multiple muscle fascicle – bundles of muscle fibers. Each individual fiber and each muscle is surrounded by a type of connective tissue layer of fascia. Muscle fibers are formed from the cell fusion of developmental myoblasts in a process known as myogenesis resulting in long cells. In these cells, the cell nucleus, termed myonuclei, are located along the inside of the sarcolemma. Muscle fibers also have multiple mitochondria to meet energy needs.
Muscle fibers are in turn composed of myofibrils. The myofibrils are composed of actin and myosin filaments called , repeated in units called sarcomeres, which are the basic functional, contractile units of the muscle fiber necessary for muscle contraction. Muscles are predominantly powered by the Redox of and , but anaerobic chemical reactions are also used, particularly by fast twitch fibers. These chemical reactions produce adenosine triphosphate (ATP) molecules that are used to power the movement of the .
Skeletal muscle comprises about 35% of the body of humans by weight. The functions of skeletal muscle include producing movement, maintaining body posture, controlling body temperature, and stabilizing joints. Skeletal muscle is also an Endocrine system. Under different physiological conditions, subsets of 654 different proteins as well as lipids, amino acids, metabolites and small RNAs are found in the secretome of skeletal muscles.
Skeletal muscles are substantially composed of contractile Muscle cell (myocytes). However, considerable numbers of resident and infiltrating mononuclear cells are also present in skeletal muscles. 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. By comparison, the mononuclear cells in muscles are much smaller. Some of the mononuclear cells in muscles are endothelial cells (which are about 50–70 μm long, 10–30 μm wide and 0.1–10 μm thick), macrophages (21 μm in diameter) and (12-15 μm in diameter). 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.
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 the endocrine system functions of muscle, described subsequently, below.
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 the tendon 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 as deep fascia. Deep fascia specialises within muscles to enclose each muscle fiber as endomysium; each muscle fascicle as perimysium, and each individual muscle as epimysium. Together these layers are called mysia. Deep fascia also separates the groups of muscles into muscle compartments.
Two types of found in muscles are , and Golgi tendon organs. Muscle spindles are located in the muscle belly. Golgi tendon organs are located at the myotendinous junction that inform of a muscle tension.
Skeletal muscle fibers are with the Cell nucleus often referred to as myonuclei. This occurs during myogenesis with the cell fusion of myoblasts each contributing a nucleus. Fusion depends on muscle-specific proteins known as called myomaker and myomerger.
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. A muscle fiber for example in the human biceps with a length of 10 cm can have as many as 3,000 nuclei. Unlike in a non-muscle cell where the nucleus is centrally positioned, the myonucleus is elongated and located close to the sarcolemma. The myonuclei are quite uniformly arranged along the fiber with each nucleus having its own myonuclear domain where it is responsible for supporting the volume of cytoplasm in that particular section of the myofiber.
A group of muscle known as myosatellite cells, also satellite cells are found between the basement 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.
The fibers in run at an angle to the axis of force generation. This pennation 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 the physiological cross-sectional area (PCSA). This effect is known as fiber 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. 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 are unipennate, bipennate, and multipennate. 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.
| + Various Properties of Different Fiber Types |
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. (2023). 9781947172043, OpenStax CNX. ISBN 9781947172043
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.
The slow twitch fibers generate energy for ATP re-synthesis by means of a long term system of aerobic 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. Fibers that become slow-twitch develop greater numbers of mitochondria and capillaries making them better for prolonged work. (2025). 9780736045179, Human Kinetics. ISBN 9780736045179
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. Among different species there is much variation in the proportions of muscle fiber types.
Sedentary men and women (as well as young children) have 45% type II and 55% type I fibers. 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.
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. 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.
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, a subtype B or b is not expressed in humans by either method. 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, 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 Vs. MHC fiber types |
| MHC Iβ |
| MHC Iβ > MHC IIa |
| MHC IIa > MHC Iβ |
| MHC IIa |
| MHC IIa > MHC IIx |
| MHC IIx > MHC IIa |
| 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. Glycolysis, 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 correlated in vivo. For instance, ATPase fiber type is related to contraction speed, because high ATPase activity allows faster crossbridge cycling. 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.
In fish, different fiber types are expressed at different water temperatures. 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.
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.
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. 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.
The sarcomere is attached to other organelles such as the mitochondria by intermediate filaments in the cytoskeleton. The costamere attaches the sarcomere to the sarcolemma.
Every single organelle and macromolecule of a muscle fiber is arranged to ensure that it meets desired functions. The cell membrane is called the sarcolemma with the cytoplasm known as the sarcoplasm. 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 the mitochondria.
While the muscle fiber does not have smooth endoplasmic cisternae, it contains sarcoplasmic reticulum. The sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of the calcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known as terminal 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). 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 a triad.
During development, (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 of connective tissue frameworks, usually formed from the somatic lateral plate mesoderm. Myoblasts follow chemical signals to the appropriate locations, where they fuse into elongated multinucleated skeletal muscle cells.
Between the tenth and the eighteenth weeks of gestation, all muscle cells have fast myosin heavy chains; two myotube types become distinguished in the developing fetus – 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. (2025). 9780736045179, Human Kinetics. ISBN 9780736045179
Fiber types are established during embryonic development and are remodelled later in the adult by neural and hormonal influences. The population of satellite cells present underneath the basal lamina is necessary for the postnatal development of muscle cells.
Muscle also functions to produce body heat. Muscle contraction is responsible for producing 85% of the body's heat. This heat produced is as a by-product of muscular activity, and is mostly wasted. As a homeostatic response to extreme cold, muscles are signaled to trigger contractions of shivering in order to generate heat.
In addition to the actin and myosin in the that make up the contractile , there are two other important regulatory proteins – troponin and tropomyosin, 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's sarcoplasmic reticulum releases 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-dependent cross-bridge cycling and shortening of the muscle.
In addition, muscles react to reflex action 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 the Spinal cord. 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 in correspond with neuron groups along the primary motor cortex of the brain's cerebral cortex. Commands are routed through the basal ganglia and are modified by input from the cerebellum before being relayed through the pyramidal tract to the spinal cord and from there to the motor end plate at the muscles. Along the way, feedback, such as that of the extrapyramidal system contribute signals to influence muscle tone and response.
Deeper muscles such as those involved in Human position often are controlled from nuclei in the brain stem and basal ganglia.
Skeletal muscle uses more calories than other organs. At rest it consumes 54.4 kJ/kg (13.0 kcal/kg) per day. This is larger than adipose tissue (fat) at 18.8 kJ/kg (4.5 kcal/kg), and bone at 9.6 kJ/kg (2.3 kcal/kg).
| +Grading of muscle strength |
| No contraction |
| Trace of contraction, but no movement at the joint |
| Movement at the joint with gravity eliminated |
| Movement against gravity, but not against added resistance |
| Movement against external resistance, but less than normal |
| Normal strength |
Vertebrate muscle typically produces approximately of force per square centimeter of muscle cross-sectional area when isometric and at optimal length. Some invertebrate muscles, such as in crab claws, have much longer 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 either mechanomyography or phonomyography, be measured in 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 upon length, shortening speed, cross sectional area, Pennate muscle, sarcomere length, myosin isoforms, and neural activation of . Significant reductions in muscle strength can indicate underlying pathology, with the chart at right used as a guide.
The maximum holding time for a contracted muscle depends on its supply of energy and is stated by Rohmert's law to exponentially decay from the beginning of exertion.
Contracting muscles produce vibration and sound. 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).[2], Peak Performance – Endurance training: understanding your slow twitch muscle fibers will boost performance 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 the tensor tympani muscle of the middle ear. The rumbling sound can also be heard when the neck or jaw muscles are highly tensed.
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 and mitochondrial 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 factor serum response factor from the structural protein titin, leading to altered muscle growth.
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. On the contrary, anaerobic exercise is associated with activities of high intensity but short duration, such as sprinting or weight training. The anaerobic activities predominately use Type II, fast-twitch, muscle fibers. Type II muscle fibers rely on Gluconeogenesis for energy during anaerobic exercise. 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 and rock climbing.
The presence of lactic 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. 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 to pyruvate. 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.
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 by eccentric contraction, or unaccustomed training levels. Since lactic acid disperses fairly rapidly, it could not explain pain experienced days after exercise.
Symptoms of muscle diseases may include Muscle weakness, spasticity, myoclonus and myalgia. Diagnostic procedures that may reveal muscular disorders include testing creatine kinase levels in the blood and electromyography (measuring electrical activity in muscles). In some cases, muscle biopsy may be done to identify a myopathy, as well as genetic testing to identify DNA abnormalities associated with specific myopathies and dystrophies.
A non-invasive elastography 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 of actomyosin Protein filament along the axis of the muscle. During contraction, the muscle shortens along its length and expands across its width, producing vibrations at the surface.
Biological factors such as age and hormone levels can affect muscle hypertrophy. During puberty in males, hypertrophy occurs at an accelerated rate as the levels of growth-stimulating produced by the body increase. Natural hypertrophy normally stops at full growth in the late teens. As testosterone is one of the body's major growth hormones, on average, men find hypertrophy much easier to achieve than women. Taking additional testosterone or other 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 called cross education.
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. Such consequences are also noted in some mammals following hibernation.
Many diseases and conditions including cancer, AIDS, and heart failure can cause muscle loss known as cachexia.
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 via electromyography (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 the hyperpolarization of the motor axons 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 of force generated, and an indicator of muscle fatigue. 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. In research using EMG, a maximal 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.
Research into the development of artificial muscles includes the use of electroactive polymers.
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 the Stroop effect. 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. 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.
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 of Uniprot or Exocarta, 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. The main pathways found to be affected by secreted exercise-regulated proteins were related to cardiac, Cognition, kidney and platelet functions.
Gene expression in muscle is largely regulated, as in tissues generally, by regulatory DNA sequences, especially enhancers. Enhancers are non-coding sequences in the genome that activate the expression of distant target genes, by looping around and interacting with the promoters of their target genes (see Figure "Regulation of transcription in mammals"). As reported by Williams et al., the average distance in the loop between the connected enhancers and promoters of genes is 239,000 nucleotide bases.
In a study by Lindholm et al., twenty-three individuals who were about 27 years old and sedentary volunteered to have endurance 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 the vastus 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 significant DNA methylation changes at 4,919 sites across the genome. The sites of altered DNA methylation were predominantly in enhancers. Transcriptional analysis, using RNA-Seq, identified 4,076 differentially expressed genes.
The transcriptionally upregulated genes were associated with enhancers that had a significant decrease in DNA 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.
Nucleosomes consist of four pairs of histone proteins in a tightly assembled core region plus up to 30% of each histone remaining in a loosely organized peptide tail (only one tail of each pair is shown). The pairs of histones, H2A, H2B, H3 and H4, each have (K) in their tails, some of which are subject to post-translational modifications consisting, usually, of acetylations Ac and methylations {me}. The lysines (K) are designated with a number showing their position as, for instance, (K4), indicating lysine as the 4th amino acid from the amino (N) end of the tail in the histone protein. The particular acetylations Ac and methylations {Me} shown are those that occur on nucleosomes close to, or at, some DNA regions undergoing transcriptional activation of the DNA wrapped around the nucleosome.]]
As indicated above, after exercise, Epigenetics alterations to enhancers alter long-term Gene expression of hundreds of muscle genes. This includes genes producing proteins secreted into the systemic circulation, many of which may act as endocrine messengers. Six sedentary, about 23 years old, Caucasian males provided vastus 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 persistently epigenetics altered. The alterations altered acetylations and deacetylations of the histone tails located in the enhancers controlling the genes with altered expression.
Up-regulated genes were associated with epigenetic acetylations added at histone 3 lysine 27 (H3K27ac) of nucleosomes located at their enhancers. Down-regulated genes were associated with the removal of epigenetic acetylations at H3K27 in nucleosomes located at their enhancers (see Figure "A nucleosome with histone 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. 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.
Walking, using skeletal muscles, affects mortality
Paluch et al. compared the average number of steps Walking per day to the risk of Mortality rate, 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.
Skeletal muscle secretome alters with exercise
Williams et al. obtained biopsies of a 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.
Exercise-trained effects are mediated by epigenetic mechanisms
Between 2012 and 2019, at least 25 reports indicated a major role of Epigenetics mechanisms in skeletal muscle responses to exercise. Epigenetic alterations often occur by DNA methylation or removing methyl groups from the cytosines of DNA, especially at CpG sites. Methylations of cytosines can cause the DNA to be compacted into heterochromatin, thus inhibiting access of other molecules to the DNA. Epigenetic alterations also often occur through acetylations or deacetylations of the Histone code tails within chromatin. DNA in the nucleus generally consists of segments of 146 base pairs of DNA wrapped around eight tightly connected (and each histone also has a loose tail) in a structure called a nucleosome and one segment of DNA is connected to an adjacent DNA segment on a nucleosome by linker DNA. When histone tails are acetylated, they usually cause loosening of the DNA around the nucleosome, leading to increased accessibility of the DNA.
Exercise-induced regulation of genes in muscles
[[File:Regulation of transcription in mammals.jpg|thumb|upright=1.35|
Regulation of transcription in mammals. An active enhancer regulatory region is enabled to interact with the promoter region of its target gene by formation of a chromosome loop. This can allow initiation of messenger RNA (mRNA) synthesis by RNA polymerase II (RNAP II) bound to the promoter at the transcription start site of the gene. The loop is stabilized by one architectural protein anchored to the enhancer and one anchored to the promoter, and these proteins are joined together to form a dimer (red zigzags). Specific regulatory transcription factors bind to DNA sequence motifs on the enhancer. General transcription factors bind to the promoter. When a transcription factor is activated by a signal (here indicated as phosphorylation shown by a small red star on a transcription factor on the enhancer), the enhancer is activated and can now activate its target promoter. The active enhancer is transcribed on each strand of DNA in opposite directions by bound RNAP IIs. Mediator (a complex consisting of about 26 proteins in an interacting structure) communicates regulatory signals from the enhancer DNA-bound transcription factors to the promoter.]]
Exercise-induced alteration to gene expression by DNA methylation or demethylation
Endurance muscle training alters muscle gene expression by epigenetic DNA methylation or de-methylation of within enhancers.
Exercise-induced long-term alteration of gene expression by histone acetylation or deacetylation
[[File:Histone tails set for transcriptional activation.jpg|thumb|upright=1.35|
A nucleosome with histone tails set for transcriptional activation....DNA in the nucleus generally consists of segments of 146 base pairs of DNA wrapped around connected to adjacent nucleosomes by linker DNA.
See also
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