Muscles contain many different systems on which the  evolutionary selection  of preflex stabilization can operate. The  deltoid muscle , for example, consists of at least seven segments with different bone attachments and neural control. [ 8 ]  Within each muscle segment, there exists a complex internal structure that goes down to one in which each muscle unit consists of a tendon,  aponeurosis , and a  fascicle  of active contractile and passive elements. [ 4 ]  Another source of variation is in the internal architecture of the fiber orientation relative to a muscle's line of action, for example, as found in  pennate muscles . [ 9 ]  The complexities of the different visco-elastic length- and velocity-force relationships of these subparts provides the opportunity for the adaptive selection of structurally complex muscle biocomposites with highly task-tuned nonlinear visco-elastic length- velocity- force relationships. This nature of muscles to be composite structures thus provides the adaptive opportunity for evolution to modify the visco-elastic reactions of the musculoskeletal system so they counteract perturbations without the need for spinal or higher levels of control.


Helmeted guineafowl  like many other  bipedal  birds  walk  upon rough ground. When a guineafowl's leg steps into a hole (a common disruption against which evolution has tuned the nonlinear visco-elastic properties of its musculoskeletal system), a momentarily uncommanded velocity and length change in the muscles that span its leg joints occurs. This length/velocity discrepancy interacts with the nonlinear length and velocity-force relationships that have evolved in response to such a disruption with the result that the leg extends further into the hole, and thus keeps the bird's body stable and upright. [ 10 ]


It is the intrinsic musculoskeletal properties of a  frog 's leg, not neurally mediated spinal reflexes, that stabilize its wiping movements at irritants when the leg movement is instigated. [ 11 ]


A human example of a preflex stabilization occurs when a person explosively  jumps  up from a  squat position , and the leg muscles act to provide a minimal time delay against perturbations from the vertical. [ 6 ]


A  protein supplement  is a  dietary supplement  or a  bodybuilding supplement , and usually comes in the form of a  protein bar , protein powder, and even readily available as a protein shake. Usually made from whey, plant, and/or meat sources.


Protein supplements are extracts or concentrates of high protein foodstuffs, used in bodybuilding and as dietary supplements to fulfill protein intake in a lean and pure source of proteins and  amino acids . They have three main variants: concentrate (food is taken and concentrated into a smaller volume with some fat and carb present), isolate (proteins and amino acids are completely isolated, mostly leaving proteins and amino acids), and hydrolyze (a protein supplement is exposed to enzymes and partially digested). Some protein supplements contain digestive enzymes as an additive for digestion and absorption.


A meta-study found that in the first few weeks of strength training with untrained individuals, changes in  lean body mass  and  muscle strength  during the initial weeks of  strength training  are not influenced by the protein supplementation, but after the first few weeks, protein supplementation “may promote muscle hypertrophy and enhance gains in muscle strength in both untrained and trained individuals” [ 1 ]  Also,  whey-protein  supplementation in  overweight  individuals may reduce the  body weight , total  fat mass  and risk factors for  cardiovascular diseases . [ 2 ]


When combined with  strength training , protein supplementation promotes greater gains in lean body mass and muscle strength as the intensity, frequency, and duration of strength training increases. [ 1 ]  It increases the  muscles' strength  and  size , during prolonged strength training in healthy adults. [ 3 ]  A meta-study concluded that intake of protein supplements higher than around 1.6 g/kg/day do not further improve the gains in  FFM (fat free mass) [ 3 ]  “at least for younger individuals”, [ 3 ]  with a  confidence interval  from 1.03 to 2.20 [ 3 ]  so “it may be prudent to recommend ~2.2 g protein/kg/d for those seeking to maximize resistance training-induced gains in FFM”. [ 3 ]


As people get older, aging reduces the effect of protein intake, and experts in the field of protein and aging recommend a protein intake between 1.2 and 2.0 g/kg/day or higher for elderly adults. [ 4 ] [ 5 ] [ 6 ] [ 7 ]  Higher-than-ADA protein recommendations are especially important if they have acute or chronic diseases.  [ 8 ]  Increased  resistance training  also helps balance aging's negative effect on muscle mass. [ 3 ]


A study group concluded: "Older people with severe kidney disease (i.e., estimated  GFR  less than 30 mL/min/1.73m 2 ), but who are not on dialysis, are an exception to this rule; these individuals may need to limit protein intake." [ 8 ]


Past studies propose that spreading protein intake through the day (with a maximum of 30g at a time) achieves maximal total stimulation of muscle protein synthesis. [ 9 ] [ 10 ]  However, recent studies suggest that protein intake for muscle gain can be taken either throughout the day or at one time, if that is more convenient. [ 11 ]


There is no evidence supporting specific pre/post-workout timing for protein-supplement intakes, despite the widely held belief that pre- or post-workout protein supplementation would be more effective. [ 12 ]


Nutritional status can be altered in people living with  chronic kidney disease (CKD).  There is moderate-certainty evidence that regular consumption of oral protein-based nutritional supplements may increase serum  albumin , a protein that can be lower in people with CKD, due to increased loss in urine and malnutrition. Improvements in albumin following protein supplementation may be greater in those who require hemodialysis or who are malnourished. [ 13 ]  Pre-albumin levels and mid-arm circumference measurements may also be increased following supplementation, though the certainty of evidence is low. [ 13 ]  Although these indicate possible improvements in nutritional status, it is unclear whether protein supplements affect quality of life, life expectancy, inflammation or body composition. [ 13 ]


Pyrometallide gels  are types of  gels  based on  pyromellitamide  molecules. [ 1 ] [ 2 ]  Such gels being developed which will enable the repair of severed  muscles  and  spinal cords  in patients.


These types of  artificial muscles  are made possible by creating  synthetic materials  which are very similar to the ones which make up human tissues and cells. These artificial materials are so similar that the body does not reject the material and instead allows normal  cell growth  in the materials which eventually become absorbed into the body.


The gel molecule is composed of a tetra-alkane benzene-1,2,4,5-tetracarboxamide. The gel structure is made up of millions of tiny fibres, which form a 3D mesh by trapping a  liquid  in the same way that a  sponge  absorbs water, to form a solid. The unique feature of self-assembled gels is that  chemical reactions  are not required to form the fibres; it is simply a case of heating them up in a liquid and waiting for them to set.


There is huge range of potential applications for these gels. Aside from the artificial muscles, these gels could also be used for  drug delivery  in  cancer  patients, where they can injected into the patient, and the gel will slowly release a constant stream of anti-cancer drugs in the body. There are also applications for computer and television screens, where gels are used for  LCD  screens. These gels could lower the  manufacturing  costs and be used to construct  flexible display  screens.


This  pharmacology -related article is a  stub . You can help Wikipedia by  expanding it .


Reciprocal inhibition  is a  neuromuscular  process in which  muscles  on one side of a joint relax to allow the contraction of muscles on the opposite side, enabling smooth and coordinated movement. [ 1 ]  This concept, introduced by  Charles Sherrington , a pioneering  neuroscientist , is also referred to as  reflexive antagonism  in some allied health fields. Sherrington, one of the founding figures in neurophysiology, observed that when the central nervous system signals an agonist muscle to contract, inhibitory signals are sent to the antagonist muscle, encouraging it to  relax  and reduce resistance. This mechanism, known as reciprocal inhibition, is essential for efficient movement and helps prevent muscle strain by balancing forces around a joint. [ 2 ]


Joints are controlled by two opposing sets of muscles called  extensors  and  flexors , that work in synchrony for smooth movement. When a muscle spindle is stretched, the  stretch reflex  is activated, and the opposing muscle group must be inhibited to prevent it from working against the contraction of the homonymous muscle. This inhibition is accomplished by the actions of an inhibitor interneuron in the spinal cord. [ 3 ]


The afferent of the muscle spindle bifurcates in the spinal cord. One branch innervates the  alpha motor neuron  that causes the homonymous muscle to contract, producing the reflex. The other branch innervates the inhibitory interneuron, which then innervates the  alpha motor neuron  that synapses onto the opposing muscle. Because the interneuron is inhibitory, it prevents the opposing  alpha motor neuron  from firing, thereby reducing the contraction of the opposing muscle. Without this reciprocal inhibition, both groups of muscles might contract simultaneously and work against each other.


If opposing muscles were to contract at the same time, a muscle tear can occur. This may occur during physical activities such as running, during which opposing muscles engage and disengage sequentially to produce coordinated movement. Reciprocal inhibition facilitates ease of movement and is a safeguard against injury. However, if a "misfiring" of motor neurons occurs, causing simultaneous contraction of opposing muscles, a tear can occur. For example, if the  quadriceps femoris  and  hamstring  contract simultaneously at a high intensity, the stronger muscle (traditionally the quadriceps) overpowers the weaker muscle group (hamstrings). This can result in a common muscular injury known as a  pulled hamstring , more accurately called a  muscle strain .


The phenomenon is fleeting, incomplete, and weak. For example, when the  triceps brachii  is stimulated, the  biceps  is reflexively inhibited. The incompleteness of the effect is related to  postural  and functional tone. Also, some reflexes  in vivo  are  polysynaptic , with entire muscle groups responding to  noxious stimuli .


As the body ages, the control of voluntary inhibition decreases in conjunction with the torque of the synapse as joints stiffen and their motor output is reduced. However, this reduction in ability tends to be insignificant. [ 4 ]


Reciprocal inhibition is the basic original notion behind indirect  muscle energy techniques . While this notion is now understood to be incomplete, the clinical mechanism of reflexive antagonism continues to be useful in physical therapy.


Muscle energy techniques that use reflexive antagonism, such as rapid deafferentation techniques, are  medical guideline  techniques and protocols that make use of reflexive pathways and reciprocal inhibition as a means of switching off inflammation, pain, and protective spasm for entire synergistic muscle groups or singular muscles and  soft tissue  structures.


René Descartes  (1596–1650) was one of the first to conceive a model of  reciprocal innervation  (in 1626) as the principle that provides for the control of  agonist  and  antagonist   muscles .  Reciprocal innervation describes skeletal muscles as existing in antagonistic pairs, with contraction of one muscle producing forces opposite to those generated by contraction of the other. For example, in the human  arm , the  triceps  acts to  extend  the lower arm outward while the  biceps  acts to  flex  the lower arm inward. To reach optimum efficiency, contraction of opposing muscles must be inhibited while muscles with the desired action are excited. This reciprocal innervation occurs so that the contraction of a muscle results in the simultaneous relaxation of its corresponding antagonist.


A common example of reciprocal innervation, is the effect of the  nociceptive  (or nocifensive) reflex, or defensive response to pain, otherwise commonly known as the  withdrawal reflex ; a type of involuntary action of the body to remove the body part from the vicinity of an offending object by contracting the appropriate muscles (usually flexor muscles), while relaxing the extensor muscles, allowing smooth movement.


The concept of reciprocal innervation as applicable to the  eye  is also known as  Sherrington's law  (after  Charles Scott Sherrington ), wherein increased innervation to an  extraocular muscle  is accompanied by a simultaneous decrease in innervation to its specific antagonist, such as the medial rectus and the lateral rectus in the case of an eye looking to one side of the midline. When looking outward or laterally, the lateral rectus of one eye must contract via increased innervation, while its antagonist, the medial rectus of the same eye - shall relax. The converse would occur in the other eye, both eyes demonstrating the law of reciprocal innervation. [ 1 ]


The significance of Descartes’ Law of Reciprocal Innervation has been additionally highlighted by recent research and applications of  bioengineering  concepts, such as optimal control and quantitative models of the motor impulses sent by the brain to control eye motion.


In some animals, the male  penis  possesses a  muscle  enabling  retraction  into the  prepuce .


The retractor penis muscle occurs in  marsupials  and  carnivorans , but it is absent in humans. [ 1 ]  A  stag's penis  forms an S-shaped curve when it is not erect, and is retracted into its  preputial sheath  by the retractor penis muscle. [ 2 ]


In  Tandonia , the retractor penis inserts at the boundary between the penis and epiphallus. [ 3 ]


In stallions , the retractor penis muscle is relatively underdeveloped. [ 4 ]  The retractor muscle contracts to retract the penis into the sheath and relaxes to allow the penis to extend from the sheath. [ 5 ]


In bulls , protrusion is not affected much by erection, but more by relaxation of the retractor penis muscle and straightening of the  sigmoid flexure . [ 4 ]


A  rhabdosphincter  (from  Greek   rhabdos  meaning "rod") is a  sphincter  consisting of  striated muscle  fibres. [ 1 ]  The muscle is a part of the  external urethral sphincter  that continues  superiorly  as a trough-like extension running vertically across the  anterior  aspect of the  prostate  to reach the  neck of the bladder . [ 2 ] [ 3 ]


Widely used in the  human factors and ergonomics  field,  Rohmert's law  states that the maximum  force  one's  muscles  can exert  decreases exponentially  from the time one begins continuously exerting the force. It is commonly used to calculate "maximum holding time" for any particular task.


Maximum force decays exponentially due to the amount of  energy  (in the form of  oxygen  and  ATP ) the body is able to supply to the muscles. The  circulatory systems  keeps muscles flooded in  nutrients  at all times, so that muscles have a supply of fuel-ready to burn at any given moment. A task requiring maximum force burns a large amount of those nutrients at the onset of the task; the circulatory system is then unable to replenish the nutrients at a rate fast enough to maintain the maximum force for long. As a result, the maximum force the muscle is capable of producing is limited by the bottleneck in  nutrient  availability, and decreases exponentially.


Imagine a theoretical  arm wrestling  match with two perfectly matched opponents, each exactly as strong as the other. They both begin the match by exerting maximum force on each other's hands, but very soon, their arms get fatigued and the actual force being exerted on each other's hands drops off quickly. They are still exerting as much force as they can, but their muscles are burning energy faster than can be replenished, and their maximum force is decreasing exponentially. Eventually, their arms are completely fatigued; they are basically just holding hands and applying what little force their muscles can muster, wondering when the other will give up.


Rohmert's law suggests that, for example, static gripping loads be not more than 15% of the load required for a squeeze-operated tool. [ 1 ]


While Rohmert's law applies to  maximum  force, the inverse is true as well; the less force one is asked to exert, the longer one will be able to exert that force before their muscles become fatigued. If one is asked to exert zero force, they can theoretically hold the position indefinitely.


Rohmert's law is true across all humans. While everyone has a different initial maximum force they can apply, their maximum force will decrease according to the same exponential curve as everyone else.


A  sarcomere  (Greek σάρξ  sarx  "flesh", μέρος  meros  "part") is the smallest functional unit of  striated muscle tissue . [ 1 ]  It is the repeating unit between two Z-lines.  Skeletal muscles  are composed of tubular muscle cells (called muscle fibers or myofibers) which are formed during   embryonic   myogenesis . Muscle fibers contain numerous tubular  myofibrils . Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. The  costamere  is a different component that connects the sarcomere to the  sarcolemma .


Two of the important proteins are  myosin , which forms the thick filament, and  actin , which forms the thin filament. Myosin has a long fibrous tail and a globular head that binds to actin. The  myosin head  also binds to  ATP , which is the source of energy for muscle movement. Myosin can only bind to actin when the binding sites on actin are exposed by calcium ions.


Actin molecules are bound to the Z-line, which forms the borders of the sarcomere. Other bands appear when the sarcomere is relaxed. [ 2 ]


The myofibrils of  smooth muscle  cells are not arranged into sarcomeres.


The sarcomeres give  skeletal  and  cardiac muscle  their  striated appearance , [ 2 ]  which was first described by  Van Leeuwenhoek . [ 3 ]


The relationship between the proteins and the regions of the sarcomere are as follows:


The protein  tropomyosin  covers the myosin-binding sites of the actin molecules in the muscle cell.  For a muscle cell to contract, tropomyosin must be moved to uncover the binding sites on the actin.  Calcium ions bind with  troponin C  molecules (which are dispersed throughout the tropomyosin protein) and alter the structure of the tropomyosin, forcing it to reveal the cross-bridge binding site on the actin.


The concentration of calcium within muscle cells is controlled by the  sarcoplasmic reticulum , a unique form of  endoplasmic reticulum  in the  sarcoplasm .


Muscle cells are stimulated when a  motor neuron  releases the neurotransmitter  acetylcholine , which travels across the  neuromuscular junction  (the synapse between the terminal button of the neuron and the muscle cell).   Acetylcholine  binds to a post-synaptic  nicotinic acetylcholine receptor . A change in the receptor conformation allows an influx of  sodium  ions and initiation of a post-synaptic  action potential . The action potential then travels along  T-tubules  (transverse tubules) until it reaches the sarcoplasmic reticulum. Here, the depolarized membrane activates voltage-gated  L-type calcium channels , present in the plasma membrane. The L-type calcium channels are in close association with  ryanodine receptors  present on the sarcoplasmic reticulum. The inward flow of calcium from the L-type calcium channels activates ryanodine receptors to release calcium ions from the sarcoplasmic reticulum. This mechanism is called  calcium-induced calcium release  (CICR). It is not understood whether the physical opening of the L-type calcium channels or the presence of calcium causes the ryanodine receptors to open. The outflow of calcium allows the myosin heads access to the actin cross-bridge binding sites, permitting muscle contraction. [ 5 ]


Muscle contraction ends when calcium ions are pumped back into the sarcoplasmic reticulum, allowing the contractile apparatus and, thus, muscle cell to relax.


Upon muscle contraction, the A-bands do not change their length (1.85 micrometer in mammalian skeletal muscle), [ 5 ]  whereas the I-bands and the H-zone shorten. This causes the Z-lines to come closer together.


At rest, the  myosin head  is bound to an  ATP  molecule in a low-energy configuration and is unable to access the cross-bridge binding sites on the actin.  However, the myosin head can hydrolyze ATP into  adenosine diphosphate  (ADP) and an inorganic phosphate ion.  A portion of the energy released in this reaction changes the shape of the myosin head and promotes it to a high-energy configuration.  Through the process of binding to the actin, the myosin head releases ADP and an inorganic phosphate ion, changing its configuration back to one of low energy.  The myosin remains attached to actin in a state known as  rigor , until a new ATP binds the myosin head. This binding of ATP to myosin releases the actin by cross-bridge dissociation. The ATP-associated myosin is ready for another cycle, beginning with hydrolysis of the ATP.


The A-band is visible as dark transverse lines across myofibers; the I-band is visible as lightly staining transverse lines, and the Z-line is visible as dark lines separating sarcomeres at the light-microscope level.


Most muscle cells can only store enough ATP for a small number of muscle contractions.  While muscle cells also store  glycogen , most of the energy required for contraction is derived from  phosphagens .  One such phosphagen,  creatine phosphate , is used to provide ADP with a phosphate group for ATP synthesis in  vertebrates . [ 5 ]


The structure of the sarcomere affects its function in several ways.  The overlap of actin and myosin gives rise to the  length-tension curve , which shows how sarcomere  force  output decreases if the muscle is stretched so that fewer cross-bridges can form or compressed until actin filaments interfere with each other.  Length of the actin and myosin filaments (taken together as sarcomere length) affects force and velocity – longer sarcomeres have more cross-bridges and thus more force, but have a reduced range of shortening.  Vertebrates display a very limited range of sarcomere lengths, with roughly the same optimal length (length at peak length-tension) in all muscles of an individual as well as between species.   Arthropods , however, show tremendous variation (over seven-fold) in sarcomere length, both between species and between muscles in a single individual.  The reasons for the lack of substantial sarcomere variability in vertebrates is not fully known. [ citation needed ]


In anatomy and physiology,  segmental stabilizers  are the muscles which provide support across joints, as in the  multifidus  across  spinal   vertebrae . [ 1 ]


Segmental stabilizers align bones, such as the spine, so as to reduce stress during movement.  They are primarily enlisted during  functional movement  and  balance training .


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 [ 1 ]  and typically are attached by  tendons  to  bones  of a  skeleton . [ 2 ] [ 3 ]  The skeletal  muscle cells  are much longer than in the other types of muscle tissue, and are also known as  muscle fibers . [ 4 ]  The tissue of a skeletal muscle is  striated  – having a striped appearance due to the arrangement of the  sarcomeres .


A skeletal muscle contains multiple  fascicles  – 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  fusion  of developmental  myoblasts  in a process known as  myogenesis  resulting in long  multinucleated  cells. In these cells the  nuclei , termed  myonuclei , are located along the inside of the  cell membrane . 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  myofilaments , repeated in units called sarcomeres, which are the basic functional, contractile units of the muscle fiber necessary for  muscle contraction . [ 5 ]  Muscles are predominantly powered by the  oxidation  of  fats  and  carbohydrates , 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  myosin 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 an  endocrine 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 the  secretome  of skeletal muscles. [ 12 ]


Skeletal muscles are substantially composed of  multinucleated  contractile  muscle 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) and  neutrophils  (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. However, recently, interest has also focused on the different types of mononuclear cells of skeletal muscle, as well as on the  endocrine  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 as  groups of muscles  that work together to carry out an action. In the  torso  there are several  major muscle groups  including the  pectoral , and  abdominal muscles ;  intrinsic and extrinsic muscles  are subdivisions of muscle groups in the  hand ,  foot ,  tongue , and  extraocular muscles  of the  eye . Muscles are also grouped into  compartments  including  four groups in the arm ,
and the  four 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 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  sensory receptors  found in muscles are  muscle spindles , and  Golgi tendon organs . Muscle spindles are  stretch receptors  located in the muscle belly. Golgi tendon organs are  proprioceptors  located at the  myotendinous junction  that inform of a  muscle's tension .


Skeletal muscle cells are the individual contractile cells within a muscle, and are often termed as  muscle fibers . [ 3 ]  A single muscle such as the  biceps  in a young adult male contains around 253,000 muscle fibers. [ 22 ]


Skeletal muscle fibers are  multinucleated  with the  nuclei  often referred to as  myonuclei . This occurs during  myogenesis  with the  fusion  of myoblasts each contributing a nucleus. [ 23 ]  Fusion depends on muscle-specific proteins known as  fusogens  called  myomaker  and  myomerger . [ 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-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. [ 24 ] [ 25 ]


A group of muscle  stem cells  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. [ 26 ]


Muscles attach to  tendons  in a complex interface region known as the  musculotendinous junction , also known as the  myotendinous 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 of  force generation , which runs from a  muscle's origin  to its  insertion .
The usual arrangements are types of  parallel , and types of  pennate 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 in  fusiform ,  strap , and  convergent 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 the  orbicularis 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 in  pennate muscles  run at an angle to the axis of force generation. [ 29 ]  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. [ 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 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 most 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 in  myofibrils  which increase the overall size of muscle cells. Well exercised muscles can not only add more size but can also develop more  mitochondria ,  myoglobin ,  glycogen  and a higher density of  capillaries . 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 ]


Broadly there are two types of muscle fiber:  Type I , which is slow, and  Type 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, and  motor 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 ]


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 of  myoglobin  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 use  oxidative 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 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. [ 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, the  quadriceps  muscles contain ~52% type I fibers, while the  soleus  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 of  motor 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 are  histochemical  staining for  myosin ATPase  activity and  immunohistochemical  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 MHC  isoforms . [ 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, a  subtype 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.


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 correlated  in vivo . [ 44 ] [ 45 ]  For instance, ATPase fiber type is related to contraction speed, because high ATPase activity allows faster  crossbridge 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 early  development  of vertebrate embryos, growth and formation of muscle happens in successive waves or phases of  myogenesis . The myosin heavy chain  isotype  is a major determinant of the specific fiber type. In  zebrafish  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 further  differentiation  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 as  Trachemys 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, the  Prdm1  gene down-regulates the formation of new slow twitch fibers through direct and indirect mechanisms such as  Sox6  (indirect). In mice, the  Prdm1  gene is present but does not control slow muscle genes in mice through  Sox6 . [ 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 proteins  myosin , and  actin  – that are two of the  myofilaments  in the  myofibrils . The myosin forms the thick filaments, and actin forms the thin filaments, and are arranged in repeating units called  sarcomeres . The interaction of both proteins results in muscle contraction.


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. [ 5 ]


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).  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 a  triad . [ 58 ]


All muscles are derived from  paraxial mesoderm . During  embryonic development  in the process of  somitogenesis  the paraxial mesoderm is divided along the  embryo 's length to form  somites , corresponding to the  segmentation  of the body most obviously seen in the  vertebral column . [ 59 ]  Each somite has three divisions,  sclerotome  (which forms  vertebrae ),  dermatome  (which forms skin), and  myotome  (which forms muscle). The myotome is divided into two sections, the epimere and hypomere, which form  epaxial and hypaxial muscles , respectively. The only epaxial muscles in humans are the  erector spinae  and small vertebral muscles, and are innervated by the dorsal rami of the  spinal nerves . All other muscles, including those of the limbs are hypaxial, and innervated by the  ventral 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 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. [ 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 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. [ 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 is  contraction . [ 3 ]  Following contraction, skeletal muscle functions as an  endocrine  organ by secreting  myokines  – a wide range of  cytokines  and other  peptides  that act as signalling molecules. [ 62 ]  Myokines in turn are believed to mediate the health benefits of  exercise . [ 63 ]  Myokines are secreted into the bloodstream after muscle contraction.  Interleukin 6  (IL-6) is the most studied myokine, other muscle contraction-induced myokines include  BDNF ,  FGF21 , and  SPARC . [ 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 a  homeostatic  response to extreme cold, muscles are signaled to trigger contractions of  shivering  in order to generate heat. [ 66 ]


Contraction is achieved by the muscle's structural unit, the muscle fiber, and by its functional unit, the  motor unit . [ 4 ]  Muscle fibers are  excitable cells  stimulated by  motor 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 are
subject to  depolarization  by the neurotransmitter  acetylcholine , released by the motor neurons at the  neuromuscular junctions . [ 67 ]


In addition to the  actin  and  myosin   myofilaments  in the  myofibrils  that make up the contractile  sarcomeres , 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  (Ca 2+ ), 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.


Excitation contraction coupling  is the process by which a  muscular action potential  in the muscle fiber causes the  myofibrils  to contract. This process relies on a direct coupling between the  sarcoplasmic reticulum  calcium release channel  RYR1  (ryanodine receptor 1), and  voltage-gated L-type calcium channels  (identified as dihydropyridine receptors, DHPRs). DHPRs are located on the sarcolemma (which includes the surface sarcolemma and the  transverse 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 of  T-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 adjacent  sarcoplasmic 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,  Ca 2+  is released from the sarcoplasmic reticulum into the local junctional space and diffuses into the bulk cytoplasm to cause a  calcium spark . The sarcoplasmic reticulum has a large  calcium buffering  capacity partially due to a  calcium-binding protein  called  calsequestrin . The near synchronous activation of thousands of  calcium sparks  by the action potential causes a cell-wide increase in calcium giving rise to the upstroke of the  calcium transient . The  Ca 2+  released into the cytosol binds to  Troponin C  by the  actin filaments , to allow crossbridge cycling, producing force and, in some situations, motion. The  sarco/endoplasmic reticulum calcium-ATPase  (SERCA) actively pumps  Ca 2+  back into the sarcoplasmic reticulum. As  Ca 2+  declines back to resting levels, the force declines and relaxation occurs. [ 68 ]


The  efferent  leg of the  peripheral nervous system  is responsible for conveying commands to the muscles and glands, and is ultimately responsible for voluntary movement.  Nerves  move muscles in response to  voluntary  and  autonomic  (involuntary) signals from the  brain . Deep muscles, superficial muscles,  muscles of the face  and internal muscles all correspond with dedicated regions in the primary motor cortex of the  brain , directly anterior to the central sulcus that divides the frontal and parietal lobes.


In addition, muscles react to  reflexive  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  spine . 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  mammals  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  posture  often are controlled from nuclei in the  brain 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. The  sense  of where our bodies are in space is called  proprioception , 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 and  red 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's  energy  consumption. All muscle cells produce  adenosine triphosphate  (ATP) molecules which are used to power the movement of the  myosin heads . Muscles have a short-term store of energy in the form of  creatine phosphate  which is generated from ATP and can regenerate ATP when needed with  creatine kinase . Muscles also keep a storage form of glucose in the form of  glycogen . Glycogen can be rapidly converted to  glucose  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 two  lactic acid  molecules in the process (in aerobic conditions, lactate is not formed; instead  pyruvate  is formed and transmitted through the  citric acid cycle ). Muscle cells also contain globules of fat, which are used for energy during  aerobic 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 than  adipose tissue  (fat) at 18.8 kJ/kg (4.5 kcal/kg), and bone at 9.6 kJ/kg (2.3 kcal/kg). [ 70 ]


The  efficiency  of human muscle has been measured (in the context of  rowing  and  cycling ) at 18% to 26%. The efficiency is defined as the ratio of  mechanical work  output to the total  metabolic  cost, as can be calculated from oxygen consumption. This low efficiency is the result of about 40% efficiency of generating  ATP  from  food 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 its  rowing 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 using  work loop analysis .


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), and  mechanical 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  lb f ) of force per square centimeter of muscle cross-sectional area when isometric and at optimal length. [ 71 ]  Some  invertebrate  muscles, such as in crab claws, have much longer  sarcomeres  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,  pennation ,  sarcomere  length,  myosin  isoforms, and neural activation of  motor units . 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.


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 to  physiological 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 and  architectural 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 two  antagonistic muscles  at any one time. During ballistic motions such as throwing, the antagonist muscles act to 'brake' the  agonist 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 the  tensor tympani muscle  of the middle ear. The rumbling sound can also be heard when the neck or jaw muscles are highly tensed. [ citation needed ]


Skeletal muscle fiber-type phenotype in adult animals is regulated by several independent signaling pathways. These include pathways involved with the  Ras /mitogen-activated protein kinase ( MAPK ) pathway, calcineurin, calcium/calmodulin-dependent protein kinase IV, and the peroxisome proliferator γ coactivator 1 (PGC-1). The  Ras/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 Ca 2+ / calmodulin -activated  phosphatase  implicated in nerve activity-dependent fiber-type specification in skeletal muscle, directly controls the phosphorylation state of the transcription factor  NFAT , 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 MEF2  transactivator  functions and enhancing oxidative capacity through stimulation of  mitochondrial 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 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.


Physical exercise is often recommended as a means of improving  motor 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 is  muscle 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 or  weight lifting . The anaerobic activities predominately use Type II, fast-twitch, muscle fibers. [ 79 ]  Type II muscle fibers rely on glucogenesis 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  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. [ 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 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. [ 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 by  eccentric 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 termed  myopathies , while diseases of nerves are called  neuropathies . Both can affect muscle function or cause muscle pain, and fall under the umbrella of  neuromuscular disease . The cause of many myopathies is attributed to mutations in the various associated muscle proteins. [ 5 ] [ 84 ]  Some  inflammatory myopathies  include  polymyositis  and  inclusion body myositis


Neuromuscular diseases  affect the muscles and their nervous control. In general, problems with nervous control can cause  spasticity  or  paralysis , depending on the location and nature of the problem. A number of  movement disorders  are caused by  neurological disorders  such as  Parkinson's disease  and  Huntington's disease  where there is central nervous system dysfunction. [ 85 ]


Symptoms of muscle diseases may include  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   filaments  along the axis of the muscle. During  contraction , the muscle shortens along its length and expands across its width, producing  vibrations  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 through  exercise . 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. During  puberty  in males, hypertrophy occurs at an accelerated rate as the levels of growth-stimulating  hormones  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  anabolic 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 called  cross education . [ citation needed ]


Every day between one and two percent of muscle is broken down and rebuilt.  Inactivity ,  malnutrition ,  disease , and  aging  can increase the breakdown leading to  muscle atrophy  or  sarcopenia . Sarcopenia is commonly an age-related process that can cause  frailty  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 following  hibernation . [ 92 ]


Many diseases and conditions including  cancer ,  AIDS , and  heart failure  can cause muscle loss known as  cachexia . [ 93 ]


Myopathies have been modeled with cell culture systems of muscle from healthy or diseased tissue  biopsies . Another source of skeletal muscle and progenitors is provided by the  directed differentiation  of  pluripotent 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 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 . [ 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 verses 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, 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. [ 97 ]


Research into the development of  artificial muscles  includes the use of  electroactive 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 by  messenger RNA  transcription of cell type markers. Cameron et al. [ 98 ]  identified nine cell types. They include  endothelial 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 are  muscle stem cells , adjacent to muscle fiber cells. Types of  lymphoid cells  (such as B-cells and T-cells) (3%) and myeloid cells such as  macrophages  (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 the  secretome  of skeletal muscles. [ 12 ]  As described in the Wikipedia article " List of human endocrine organs and actions ", skeletal muscle is identified as an  endocrine organ  due to its secretion of  cytokines  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 after  endurance training  or  resistance 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/m 2  for males, and less than 5.42 kg/m 2  for females (levels defined as  sarcopenia  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 the  Stroop 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 steps  walked  per day to the risk of  mortality , 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 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.


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. [ 102 ]  The main pathways found to be affected by secreted exercise-regulated proteins were related to  cardiac ,  cognitive ,  kidney  and  platelet  functions.


Between 2012 and 2019, at least 25 reports indicated a major role of  epigenetic  mechanisms in skeletal muscle responses to exercise. [ 105 ]  Epigenetic alterations often occur by  adding methyl groups to cytosines in the DNA  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. [ 106 ]  Epigenetic alterations also often occur through acetylations or deacetylations of the  histone  tails within  chromatin . DNA in the nucleus generally consists of segments of 146  base pairs  of DNA wrapped around eight tightly connected  histones  (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.


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, [ 107 ]  by looping around and interacting with the  promoters  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 epigenetic  DNA methylation  or de-methylation of  CpG 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 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 sequencing , 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.


As indicated above, after exercise,  epigenetic  alterations to  enhancers  alter long-term  expression  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 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  epigentically  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 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. [ 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 ]


The  skeletal muscle pump  or  musculovenous pump  is a collection of  skeletal muscles  that aid the  heart  in the circulation of  blood . It is especially important in increasing  venous return  to the heart, [ 1 ]  but may also play a role in  arterial blood   flow .


The skeletal muscle pump is vital in negating  orthostatic intolerance  when  standing . [ 2 ]  When moving upright, the  blood volume  moves to the peripheral parts of the body. To combat this, the  muscles  involved in standing contract and help to bring  venous blood  volume to the heart. [ 1 ] [ 2 ]  The pump is important in affecting the central and local supply of blood output. [ 3 ]   Venous return ,  cardiac output , and  stroke volume  were all increased during  exercise  experiments, as well as affecting the local muscle being used, blood volume.


Between muscle relaxations, intramuscular pressure transiently returns to a level below the venous blood pressure. This allows blood from the  capillary system  to refill the veins until the next  contraction . It is postulated that this change in  pressure  may be great enough to draw blood from the arterial side to the venous side. It is hypothesized that this pressure drop during rhythmic contraction actually increases blood flow through the muscle, and may be responsible for a portion of the increase in muscle blood flow immediately at the onset of activity. [ 4 ] [ 5 ]  This explanation is attractive, because it would explain the readily observable tight coupling between muscle contraction and a rapid increase in muscle blood flow. However, recent evidence has emerged that cast doubts on this theory. Experiments have shown that a strong muscle contraction can occur without a corresponding increase in skeletal muscle blood flow. [ 6 ]  Given the proposed manner of action of the muscle pump to increase arterial blood flow, it would seem impossible for a muscle contraction and skeletal muscle  hyperemia  to be uncoupled. Another experiment recently was only able to find evidence that  vasodilation , not the skeletal muscle pump, was responsible for maintaining proper pressure and blood return. [ 7 ]  This might have to do with the lack of rigorous  physiological tests  thus far used to be able to prove the pump.


Experiments have shown the use of passive leg exercises, where only vasodilation was used, was responsible for increased blood return. [ 3 ]


The  sliding filament theory  explains the mechanism of  muscle contraction  based on muscle proteins that slide past each other to generate movement. [ 1 ]  According to the sliding filament theory, the  myosin   ( thick filaments ) of  muscle fibers  slide past the  actin  ( thin filaments ) during muscle contraction, while the two groups of filaments remain at relatively constant length.


The theory was independently introduced in 1954 by two research teams, one consisting of  Andrew Huxley  and  Rolf Niedergerke  from the  University of Cambridge , and the other consisting of  Hugh Huxley  and  Jean Hanson  from the  Massachusetts Institute of Technology . [ 2 ] [ 3 ]  It was originally conceived by Hugh Huxley in 1953. Andrew Huxley and Niedergerke introduced it as a "very attractive" hypothesis. [ 4 ]


Before the 1950s there were several competing theories on muscle contraction, including electrical attraction, protein folding, and protein modification. [ 5 ]  The novel theory directly introduced a new concept called cross-bridge theory (classically swinging cross-bridge, now mostly referred to as  cross-bridge cycle ) which explains the molecular mechanism of sliding filament. Cross-bridge theory states that actin and myosin form a protein complex (classically called  actomyosin ) by attachment of myosin head on the actin filament, thereby forming a sort of cross-bridge between the two filaments. The sliding filament theory is a widely accepted explanation of the mechanism that underlies muscle contraction. [ 6 ]


The first muscle protein discovered was myosin by a German scientist  Willy Kühne ,  who extracted and named it in 1864. [ 7 ]  In 1939 a Russian husband and wife team Vladimir Alexandrovich Engelhardt and Militsa Nikolaevna Lyubimova discovered that myosin had an enzymatic (called  ATPase ) property that can break down  ATP  to release energy. [ 8 ]   Albert Szent-Györgyi , a Hungarian physiologist, turned his focus on muscle physiology after winning the  Nobel Prize in Physiology or Medicine  in 1937 for his works on  vitamin C  and  fumaric acid . He demonstrated in 1942 that ATP was the source of energy for muscle contraction. He actually observed that muscle fibres containing myosin B shortened in the presence of ATP, but not with myosin A, the experience which he later described as "perhaps the most thrilling moment of my life." [ 9 ]  With  Brunó Ferenc   Straub , he soon found that myosin B was associated with another protein, which they called actin, while myosin A was not. Straub purified actin in 1942, and Szent-Györgyi purified myosin A in 1943. It became apparent that myosin B was a combination of myosin A and actin, so that myosin A retained the original name, whereas they renamed myosin B as actomyosin. By the end of the 1940s Szent-Györgyi's team had postulated with evidence that contraction of actomyosin was equivalent to muscle contraction as a whole. [ 10 ]  But the notion was generally opposed, even from the likes of Nobel laureates such as  Otto Fritz Meyerhof  and  Archibald Hill , who adhered to the prevailing dogma that myosin was a structural protein and not a functional enzyme. [ 3 ]  However, in one of his last contributions to muscle research, Szent-Györgyi demonstrated that actomyosin driven by ATP was the basic principle of muscle contraction. [ 11 ]


By the time  Hugh Huxley  earned his PhD from the University of Cambridge in 1952 on his research on the structure of muscle, Szent-Györgyi had turned his career into cancer research. [ 12 ]  Huxley went to  Francis O. Schmitt 's laboratory at the  Massachusetts Institute of Technology  with a post-doctoral fellowship in September 1952, where he was joined by another English post-doctoral fellow  Jean Hanson  in January 1953. Hanson had a PhD in muscle structure from  King's College, London  in 1951. Huxley had used  X-ray diffraction  to speculate that muscle proteins, particularly myosin, form structured filaments giving rise to  sarcomere  (a segment of muscle fibre). Their main aim was to use  electron microscopy  to study the details of those filaments as never done before. They soon discovered and confirmed the filament nature of muscle proteins. Myosin and actin form overlapping filaments, myosin filaments mainly constituting the A band (the dark region of a sarcomere), while actin filaments traverse both the A and I (light region) bands. [ 13 ]  Huxley was the first to suggest the sliding filament theory in 1953, stating:


"… [I]f it is postulated that stretching of the muscle takes place, not by an extension of the filaments, but by a process in which the two sets of  filaments slide  [emphasis added] past each other; extensibility will then be inhibited if the myosin and actin are linked together." [ 14 ]


Later, in 1996, Huxley regretted that he should have included Hanson in the formulation of his theory because it was based on their collaborative work. [ 15 ]


Andrew Huxley , whom  Alan Hodgkin  described as "wizard with scientific apparatus", had just discovered the mechanism of the nerve impulse ( action potential ) transmission (for which he and Hodgkin later won the Nobel Prize in Physiology or Medicine in 1963) in 1949 using his own design of  voltage clamp , and was looking for an associate who could properly dissect out muscle fibres. [ 16 ]  Upon recommendation of a close friend Robert Stämpfli, a German physician  Rolf Niedergerke  joined him at the University of Cambridge in 1952. By then he realised that the conventionally used  phase-contrast microscope  was not suitable for fine structures of muscle fibres, and thus developed his own  interference microscope . Between March 1953 and January 1954 they executed their research. [ 17 ]  Huxley recollected that at the time the only person who ever thought of sliding filaments before 1953 was  Dorothy Hodgkin  (later winner of the 1964   Nobel Prize in Chemistry ). [ 18 ]  He spent the summer of 1953 at  Marine Biological Laboratory  at Woods Hole, Massachusetts, to use electron microscope there. There he met Hugh Huxley and Hanson with whom he shared data and information on their works. They parted with an agreement that they would keep in touch, and when their aim is achieved, they would publish together, if they ever "reached similar conclusions". [ 2 ]


The sliding filament theory was born from two consecutive papers published on the 22 May 1954 issue of  Nature  under the common theme "Structural Changes in Muscle During Contraction". Though their conclusions were fundamentally similar, their underlying experimental data and propositions were different.


The first paper, written by Andrew Huxley and Rolf Niedergerke, is titled "Interference microscopy of living muscle fibres". It was based on their study of frog muscle using interference microscope, which Andrew Huxley developed for the purpose. According to them: [ 4 ]


The second paper, by Hugh Huxley and Jean Hanson, is titled "Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation". It is more elaborate and was based on their study of rabbit muscle using phase contrast and electron microscopes. According to them: [ 19 ]


In spite of strong evidence, the sliding filament theory did not gain any support for several years to come. [ 20 ]  Szent-Györgyi himself refused to believe that myosin filaments were confined to the thick filament (A band). [ 15 ]  F.O. Schmitt, whose electron microscope provided the best data, also remained sceptical of the original images. [ 21 ]  There were also immediate arguments as to the organisation of the filaments, whether the two sets (myosin and actin) of filaments were merely overlapping or continuous. It was only with the new electron microscope that Hugh Huxley confirmed the overlapping nature of the filaments in 1957. [ 22 ]  It was also from this publication that the existence of actin-myosin linkage (now called cross-bridge) was clearly shown. But he took another five years to provide evidence that the cross-bridge was a dynamic interaction between actin and myosin filaments. [ 23 ]  He obtained the actual molecular arrangement of the filaments using X-ray crystallography by teaming up with  Kenneth Holmes , who was trained by  Rosalind Franklin , in 1965. [ 24 ]  It was only after a conference in 1972 at  Cold Spring Harbor Laboratory , where the theory and its evidence were deliberated, that it became generally accepted. [ 25 ]  At the conference, as Koscak Maruyama later recalled, Hanson had to answer the criticisms by shouting, "I know I cannot explain the mechanism yet, but the sliding is a fact." [ 26 ]  The factual proofs came in the early 1980s when it could be demonstrated the actual sliding motion using novel sophisticated tools by different researchers. [ 27 ] [ 28 ] [ 29 ]


With substantial evidence, Hugh Huxley formally proposed the mechanism for sliding filament which is variously called swinging cross-bridge model, cross-bridge theory or cross-bridge model. [ 3 ] [ 30 ]  (He himself preferred the name "swinging crossbridge model", because, as he recalled, "it [the discovery] was, after all, the 1960s". [ 2 ] ) He published his theory in the 20 June 1969 issue of  Science  under the title "The Mechanism of Muscular Contraction". [ 31 ]   According to his theory, filament sliding occurs by cyclic attachment and detachment of myosin on actin filaments. Contraction occurs when the myosin pulls the actin filament towards the centre of the A band, detaches from actin and creates a force (stroke) to bind to the next actin molecule. [ 32 ]  This idea was subsequently proven in detail, and is more appropriately known as the  cross-bridge cycle . [ 33 ]


A  slow-wave potential  is a rhythmic electrophysiological event in the  gastrointestinal tract . The normal conduction of slow waves is one of the key regulators of gastrointestinal motility. [ 1 ]  Slow waves are generated and propagated by a class of pacemaker cells called the  interstitial cells of Cajal , which also act as intermediates between  nerves  and  smooth muscle cells . [ 2 ]  Slow waves generated in interstitial cells of Cajal spread to the surrounding smooth muscle cells and control motility.