Architectural gear ratio  (AGR) relates the contractile velocity of an entire muscle to the contractile velocity of a single muscle fiber. AGR is determined by the mechanical demands of a muscle during movement. Changes in pennation angle allow for variable gearing in pennate muscles. [ 12 ]  Variable pennation angle also influences whole-muscle geometry during contraction. The degree of fiber rotation determines the cross-sectional area during the course of the movement which can result in increases of the thickness or width of the muscle. [ 12 ]  Pennation angle can be modified through exercise interventions. [ 13 ]


A high gear ratio occurs when the contraction velocity of the whole muscle is much greater than that of an individual muscle fiber, resulting in a gear ratio that is greater than 1. A high gear ratio will result in low force, high velocity contractions of the entire muscle. The angle of pennation will increase during contraction accompanied by an increase in thickness. Thickness is defined as the area between the aponeuroses of the muscle. A low gear ratio occurs when the contraction velocity of the whole muscle and individual fibers is approximately the same, resulting in a gear ratio of 1. Conditions resulting in a low gear ratio include high force and low velocity contraction of the whole muscle. The pennation angle typically shows little variation. The muscle thickness will decrease.


Muscle arms  are body wall  muscle  (BWM)  membrane  extensions that connect the BWMs to the motor axons of the  dorsal  and  ventral  nerve cords in the  nematode  worm  C. elegans . Muscle arms were first described in other nematode species by  Anton Schneider  (1831 – 1890) in his "Monographie der Nematoden", published in 1866.  Subsequent work showed that muscle arms are found in C. elegans and that these structures are abnormal in unc-104, unc-5 and other mutants.  [ 1 ]


Wormatlas  - a structural anatomy of muscles, including muscle arms.


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


In  medicine , a  muscle biopsy  is a procedure in which a piece of  muscle   tissue  is removed from an  organism  and examined  microscopically . A muscle biopsy can lead to the discovery of problems with the  nervous system ,  connective tissue ,  vascular system , or  musculoskeletal system .


In humans with weakness and low muscle tone, a muscle biopsy can help distinguish between  myopathies  (where the pathology is in the muscle tissue itself) and  neuropathies  (where the pathology is at the nerves innervating those muscles). Muscle biopsies can also help to distinguish among various types of  myopathies , by microscopic analysis for differing characteristics when exposed to a variety of chemical reactions and stains. [ 1 ] [ 2 ]


However, in some cases the muscle biopsy alone is inadequate to distinguish between certain myopathies. For example, a muscle biopsy showing the nucleus pathologically located in the center of the muscle cell would indicate " centronuclear myopathy ", but research has shown that a variety of  myopathies  can cause these centronuclear biopsy appearance, and hence the specific  genetic testing  becomes increasingly important. [ 3 ] [ 4 ]
Additionally muscle biopsy is the only certain way to clarify ones muscle fiber types. I.e. by undergoing a muscle biopsy one can get a clear picture of which type of muscles dominates his/her body.


A  biopsy needle  is usually inserted into a muscle, wherein a small amount of tissue remains. Alternatively, an "open biopsy" can be performed by obtaining the muscle tissue through a small surgical incision. [ citation needed ]


Muscle coactivation  occurs when  agonist  and  antagonist muscles  (or  synergist muscles ) surrounding a joint contract simultaneously to provide joint stability, [ 1 ] [ 2 ]  and is suggested to depend crucially on supraspinal processes involved in the control of movement. [ 3 ]  It is also known as muscle cocontraction, since two muscle groups are  contracting  at the same time. It is able to be measured using  electromyography  (EMG) from the contractions that occur. The general mechanism of it is still widely unknown. It is believed to be important in joint stabilization, as well as general  motor control . [ 1 ]


Muscle coactivation allows muscle groups surrounding a joint to become more stable. This is due to both muscles (or sets of muscles) contracting at the same time, which produces compression on the joint. The joint is able to become stiffer and more stable due to this action. [ 4 ] [ 5 ]  For example, when the  biceps  and the  triceps  coactivate, the elbow becomes more stable. This stabilization mechanism is also important for unexpected loads impeded on the joint, allowing the muscles to quickly coactivate and provide stability to the joint. [ 1 ] [ 4 ]  This mechanism is controlled  neuromuscularly , which allows the muscle(s) to contract. [ 1 ]  This occurs through a  motor neuron  sending a signal (through creating  action potentials ) to the  muscle fiber  to contract by releasing  acetylcholine . [ 6 ]  When signals are sent to all muscle fibers in a muscle group, the muscle group will contract as a whole.


In the upper limbs, the stability of muscle coactivation allows for precise low-level physical tasks. [ 1 ]   An example of this would be picking up a small object. By protecting the muscles at the end of their range of motion, the direction of the fine movements is able to be changed. [ 4 ]  In the lower limbs, stability is important in upright standing balance. The coactivation of different muscle groups allows for proper balance and the ability to adjust weight and to stay upright on uneven ground. [ 7 ]  It is also believed to be important for  postural control  by stabilizing the spine. [ 1 ]  Muscle coactivation is absolutely necessary for learning a fine motor skill or for any activity involving stability. [ 7 ]  In order for muscle coactivation to occur, it must inhibit  reciprocal innervation , which occurs when a muscle contracts and the  synergist muscle  relaxes. [ 5 ]  For muscle coactivation to occur, both the muscle and synergist muscle need to contract.


Muscle coactivation is measured using a technique called  electromyography (EMG). [ 1 ]  This is performed by using surface EMG that responds to electrical activity of the muscle through the skin. [ 8 ]  Electrical activity is only present in the muscle when the muscle voluntarily contracts. [ 9 ]  When the muscle is contracted, the EMG is able to display the force of the contraction or how the nerves can respond to stimulation. [ 10 ]  An EMG of coactivation would display the agonist and antagonist muscle contracting simultaneously. Although it is believed many muscles are involved in the mechanism of coactivation, methods to measure coactivation are finite to specific instances or two muscle systems. Because of this, little is understood about the role of coactivation in a multiple muscle system. [ 1 ]


Muscle contraction  is the activation of  tension -generating sites within  muscle cells . [ 1 ] [ 2 ]  In  physiology , muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. [ 1 ]  The termination of muscle contraction is followed by  muscle relaxation , which is a return of the muscle fibers to their low tension-generating state. [ 1 ]


For the contractions to happen, the muscle cells must rely on the change in action of two types of  filaments : thin and thick filaments.


The major constituent of thin filaments is a chain formed by helical coiling of two strands of  actin , and thick filaments dominantly consist of chains of the  motor-protein   myosin . Together, these two filaments form myofibrils - the basic functional organelles in the skeletal muscle system.


In  vertebrates ,  skeletal muscle contractions  are  neurogenic  as they require  synaptic input  from  motor neurons . A single motor neuron is able to innervate multiple muscle fibers, thereby causing the fibers to contract at the same time. Once innervated, the protein filaments within each skeletal muscle fiber slide past each other to produce a contraction, which is explained by the  sliding filament theory . The contraction produced can be described as a  twitch , summation, or tetanus, depending on the frequency of  action potentials . In skeletal muscles, muscle tension is at its greatest when the muscle is stretched to an intermediate length as described by the length-tension relationship.


Unlike skeletal muscle, the contractions of  smooth  and  cardiac muscles  are  myogenic  (meaning that they are initiated by the smooth or heart muscle cells themselves instead of being stimulated by an outside event such as nerve stimulation), although they can be modulated by stimuli from the  autonomic nervous system . The mechanisms of contraction in these  muscle tissues  are similar to those in skeletal muscle tissues.


Muscle contraction can also be described in terms of two variables: length and tension. [ 1 ]  In natural movements that underlie  locomotor activity , muscle contractions are multifaceted as they are able to produce changes in length and tension in a time-varying manner. [ 3 ]  Therefore, neither length nor tension is likely to remain the same in  skeletal muscles  that contract during locomotion. Contractions can be described as  isometric  if the muscle tension changes but the muscle length remains the same. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  In contrast, a muscle contraction is described as  isotonic  if muscle tension remains the same throughout the contraction. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  If the muscle length shortens, the contraction is concentric; [ 1 ] [ 7 ]  if the muscle length lengthens, the contraction is eccentric.


Muscle contractions can be described based on two variables: force and length. Force itself can be differentiated as either tension or load. Muscle tension is the force exerted by the muscle on an object whereas a load is the force exerted by an object on the muscle. [ 1 ]  When muscle tension changes without any corresponding changes in muscle length, the muscle contraction is described as isometric. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  If the muscle length changes while muscle tension remains the same, then the muscle contraction is isotonic. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  In an isotonic contraction, the muscle length can either shorten to produce a concentric contraction or lengthen to produce an eccentric contraction. [ 1 ] [ 7 ]  In natural movements that underlie locomotor activity, muscle contractions are multifaceted as they are able to produce changes in length and tension in a time-varying manner. [ 3 ]  Therefore, neither length nor tension is likely to remain constant when the muscle is active during locomotor activity.


An isometric contraction of a muscle generates tension without changing length. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  An example can be found when the muscles of the hand and  forearm  grip an object; the  joints  of the hand do not move, but muscles generate sufficient force to prevent the object from being dropped.


In  isotonic contraction , the tension in the muscle remains constant despite a change in muscle length. [ 1 ] [ 4 ] [ 5 ] [ 6 ]  This occurs when a muscle's force of contraction matches the total load on the muscle.


In concentric contraction, muscle tension is sufficient to overcome the load, and the muscle shortens as it contracts. [ 8 ]  This occurs when the force generated by the muscle exceeds the load opposing its contraction.


During a concentric contraction, a muscle is stimulated to contract according to the  sliding filament theory . This occurs throughout the length of the muscle, generating a force at the origin and insertion, causing the muscle to shorten and changing the angle of the joint. In relation to the  elbow , a concentric contraction of the  biceps  would cause the arm to bend at the elbow as the hand moved from the leg to the shoulder (a  biceps curl ). A concentric contraction of the  triceps  would change the angle of the joint in the opposite direction, straightening the arm and moving the hand towards the leg.


In eccentric contraction, the tension generated while isometric is insufficient to overcome the external load on the muscle and the muscle fibers lengthen as they contract. [ 9 ]  Rather than working to pull a joint in the direction of the muscle contraction, the muscle acts to  decelerate  the joint at the end of a movement or otherwise control the repositioning of a load. This can occur involuntarily (e.g., when attempting to move a weight too heavy for the muscle to lift) or voluntarily (e.g., when the muscle is 'smoothing out' a movement or resisting gravity such as during downhill walking). Over the short-term,  strength training  involving both eccentric and concentric contractions appear to increase  muscular strength  more than training with concentric contractions alone. [ 10 ]  However, exercise-induced muscle damage is also greater during lengthening contractions. [ 11 ]


During an eccentric contraction of the  biceps muscle , the elbow starts the movement while bent and then straightens as the hand moves away from the  shoulder . During an eccentric contraction of the  triceps muscle , the elbow starts the movement straight and then bends as the hand moves towards the shoulder.  Desmin ,  titin , and other z-line  proteins  are involved in eccentric contractions, but their mechanism is poorly understood in comparison to  cross-bridge cycling  in concentric contractions. [ 9 ]


Though the muscle is doing a negative amount of  mechanical work , (work is being done  on  the muscle), chemical energy (of fat or  glucose , or temporarily stored in  ATP ) is nevertheless consumed, although less than would be consumed during a concentric contraction of the same force. For example, one expends more energy going up a flight of stairs than going down the same flight.


Muscles undergoing heavy eccentric loading suffer greater damage when overloaded (such as during  muscle building  or  strength training  exercise) as compared to concentric loading. When eccentric contractions are used in weight training, they are normally called  negatives . During a concentric contraction, contractile muscle  myofilaments  of  myosin  and  actin  slide past each other, pulling the Z-lines together. During an eccentric contraction, the myofilaments slide past each other the opposite way, though the actual movement of the myosin heads during an eccentric contraction is not known. Exercise featuring a heavy eccentric load can actually support a greater weight (muscles are approximately 40% stronger during eccentric contractions than during concentric contractions) and also results in greater muscular damage and  delayed onset muscle soreness  one to two days after training. Exercise that incorporates both eccentric and concentric muscular contractions (i.e., involving a strong contraction and a controlled lowering of the weight) can produce greater gains in strength than concentric contractions alone. [ 10 ] [ 12 ]  While unaccustomed heavy eccentric contractions can easily lead to  overtraining , moderate training may confer protection against injury. [ 10 ]


Eccentric contractions normally occur as a braking force in opposition to a concentric contraction to protect joints from damage. During virtually any routine movement, eccentric contractions assist in keeping motions smooth, but can also slow rapid movements such as a punch or throw. Part of training for rapid movements such as  pitching  during baseball involves reducing eccentric braking allowing a greater power to be developed throughout the movement.


Eccentric contractions are being researched for their ability to speed rehabilitation of weak or injured tendons.  Achilles tendinitis [ 13 ] [ 14 ]  and  patellar tendonitis [ 15 ]  (also known as jumper's knee or patellar tendonosis) have been shown to benefit from high-load eccentric contractions.


In  vertebrate animals , there are three types of  muscle tissues : skeletal, smooth, and cardiac.  Skeletal muscle  constitutes the majority of muscle mass in the body and is responsible for locomotor activity.  Smooth muscle  forms  blood vessels , the  gastrointestinal tract , and other areas in the body that produce sustained contractions.  Cardiac muscle  makes up the heart, which pumps blood. Skeletal and cardiac muscles are called  striated muscle  because of their striped appearance under a microscope, which is due to the highly organized alternating pattern of A bands and I bands.


Excluding reflexes, all  skeletal muscle  contractions occur as a result of signals originating in the brain. The brain sends electrochemical signals through the  nervous system  to the  motor neuron  that  innervates  several muscle fibers. [ 16 ]  In the case of some  reflexes , the signal to contract can originate in the  spinal cord  through a feedback loop with the grey matter. Other actions such as locomotion, breathing, and chewing have a reflex aspect to them: the contractions can be initiated either consciously or unconsciously.


A  neuromuscular junction  is a  chemical synapse  formed by the contact between a  motor neuron  and a  muscle fiber . [ 17 ]  It is the site in which a motor neuron transmits a signal to a muscle fiber to initiate muscle contraction. The sequence of events that results in the depolarization of the muscle fiber at the neuromuscular junction begins when an action potential is initiated in the cell body of a motor neuron, which is then propagated by  saltatory conduction  along its axon toward the neuromuscular junction. Once it reaches the  terminal bouton , the action potential causes a  Ca 2+  ion  influx into the terminal by way of the  voltage-gated calcium channels . The  Ca 2+  influx  causes  synaptic vesicles  containing the neurotransmitter  acetylcholine  to fuse with the plasma membrane, releasing acetylcholine into the  synaptic cleft  between the motor neuron terminal and the neuromuscular junction of the skeletal muscle fiber. Acetylcholine diffuses across the synapse and binds to and activates  nicotinic acetylcholine receptors  on the neuromuscular junction. Activation of the nicotinic receptor opens its intrinsic  sodium / potassium  channel, causing sodium to rush in and potassium to trickle out. As a result, the  sarcolemma  reverses polarity and its voltage quickly jumps from the resting membrane potential of -90mV to as high as +75mV as sodium enters. The membrane potential then becomes hyperpolarized when potassium exits and is then adjusted back to the resting membrane potential. This rapid fluctuation is called the end-plate potential. [ 18 ]  The voltage-gated ion channels of the sarcolemma next to the end plate open in response to the end plate potential. They are sodium and potassium specific and only allow one through. This wave of ion movements creates the action potential that spreads from the motor end plate in all directions. [ 18 ]  If action potentials stop arriving, then acetylcholine ceases to be released from the terminal bouton. The remaining acetylcholine in the synaptic cleft is either degraded by active  acetylcholine esterase  or reabsorbed by the synaptic knob and none is left to replace the degraded acetylcholine.


Excitation–contraction coupling (ECC) is the process by which a  muscular action potential  in the muscle fiber causes  myofibrils  to contract. In skeletal muscles, excitation–contraction coupling relies on a direct coupling between two key proteins, the  sarcoplasmic reticulum  (SR) calcium release channel identified as the  ryanodine receptor 1  (RYR1) and the  voltage-gated L-type calcium channel  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 (ECC) occurs when depolarization of skeletal muscles (usually through neural innervation) results in a muscle action potential. This action potential spreads across the muscle's surface and into the muscle fiber's network of  T-tubules , depolarizing the inner portion of the muscle fiber. This activates dihydropyridine receptors in the  terminal cisternae , which are in close proximity 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 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 . [ 19 ]  The action potential creates a near synchronous activation of thousands of  calcium sparks  and 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 . This bond allows the actin filaments to perform  cross-bridge cycling , producing force and, in some situations, motion.


When the desired motion is accomplished, relaxation can be achieved quickly through numerous pathways. Relaxation is quickly achieved through a Ca 2+  buffer with various cytoplasmic proteins binding to Ca 2+  with very high affinity. [ 20 ]  These cytoplasmic proteins allow for quick relaxation in fast twitch muscles. Although slower, the  sarco/endoplasmic reticulum calcium-ATPase  (SERCA) actively pumps Ca 2+  back into the sarcoplasmic reticulum, resulting in a permanent relaxation until the next action potential arrives. [ 19 ]


Mitochondria also participate in Ca 2+  reuptake, ultimately delivering their gathered Ca 2+  to SERCA for storage in the sarcoplasmic reticulum. A few of the relaxation mechanisms (NCX, Ca2+ pumps and Ca2+ leak channels) move Ca2+ completely out of the cells as well. [ 21 ]  As Ca 2+  concentration declines to resting levels, Ca2+ releases from Troponin C, disallowing cross bridge-cycling, causing the force to decline and relaxation to occur. Once relaxation has fully occurred, the muscle is able to contract again, thus fully resetting the cycle.


The  sliding filament theory  describes a process used by  muscles  to contract. It is a cycle of repetitive events that cause a thin filament to slide over a thick filament and generate tension in the muscle. [ 22 ]  It was independently developed by  Andrew Huxley  and  Rolf Niedergerke  and by  Hugh Huxley  and  Jean Hanson  in 1954. [ 23 ] [ 24 ]  Physiologically, this contraction is not uniform across the sarcomere; the central position of the thick filaments becomes unstable and can shift during contraction but this is countered by the actions of the elastic myofilament of  titin . This fine myofilament maintains uniform tension across the sarcomere by pulling the thick filament into a central position. [ 25 ]


Cross-bridge cycling is a sequence of molecular events that underlies the sliding filament theory. A  cross-bridge  is a myosin projection, consisting of two myosin heads, that extends from the thick filaments. [ 1 ]  Each myosin head has two binding sites: one for  adenosine triphosphate  (ATP) and another for actin. The binding of ATP to a myosin head detaches myosin from  actin , thereby allowing myosin to bind to another actin molecule. Once attached, the ATP is hydrolyzed by myosin, which uses the released energy to move into the "cocked position" whereby it binds weakly to a part of the actin binding site. The remainder of the actin binding site is blocked by  tropomyosin . [ 26 ]  With the ATP hydrolyzed, the cocked myosin head now contains  adenosine diphosphate  (ADP) +  P i . Two  Ca 2+  ions bind to  troponin C  on the actin filaments. The troponin- Ca 2+  complex causes tropomyosin to slide over and unblock the remainder of the actin binding site. Unblocking the rest of the actin binding sites allows the two myosin heads to close and myosin to bind strongly to actin. [ 26 ]  The myosin head then releases the inorganic phosphate and initiates a  power stroke,  which generates a force of 2 pN. The power stroke moves the actin filament inwards, thereby shortening the  sarcomere . Myosin then releases ADP but still remains tightly bound to actin. At the end of the power stroke, ADP is released from the myosin head, leaving myosin attached to actin in a rigor state until another ATP binds to myosin. A lack of ATP would result in the rigor state characteristic of  rigor mortis . Once another ATP binds to myosin, the myosin head will again detach from actin and another cross-bridge cycle occurs.


Cross-bridge cycling is able to continue as long as there are sufficient amounts of ATP and  Ca 2+  in the cytoplasm. [ 26 ]  Termination of cross-bridge cycling can occur when  Ca 2+  is  actively pumped  back into the sarcoplasmic reticulum. When  Ca 2+  is no longer present on the thin filament, the tropomyosin changes conformation back to its previous state so as to block the binding sites again. The myosin ceases binding to the thin filament, and the muscle relaxes. The  Ca 2+  ions leave the troponin molecule to maintain the  Ca 2+  ion concentration in the sarcoplasm. The active pumping of  Ca 2+  ions into the sarcoplasmic reticulum creates a deficiency in the fluid around the myofibrils. This causes the removal of  Ca 2+  ions from the troponin. Thus, the tropomyosin-troponin complex again covers the binding sites on the actin filaments and contraction ceases.


The strength of skeletal muscle contractions can be broadly separated into  twitch , summation, and  tetanus . A twitch is a single contraction and relaxation cycle produced by an action potential within the muscle fiber itself. [ 27 ]  The time between a stimulus to the motor nerve and the subsequent contraction of the innervated muscle is called the  latent period , which usually takes about 10 ms and is caused by the time taken for nerve action potential to propagate, the time for chemical transmission at the neuromuscular junction, then the subsequent steps in excitation-contraction coupling. [ 28 ]


If another muscle action potential were to be produced before the complete relaxation of a muscle twitch, then the next twitch will simply sum onto the previous twitch, thereby producing a  summation . [ 29 ]  Summation can be achieved in two ways: [ 30 ]   frequency summation  and  multiple fiber summation . In  frequency summation , the force exerted by the skeletal muscle is controlled by varying the frequency at which  action potentials  are sent to muscle fibers. Action potentials do not arrive at muscles synchronously, and, during a contraction, some fraction of the fibers in the muscle will be firing at any given time. In a typical circumstance, when humans are exerting their muscles as hard as they are consciously able, roughly one-third of the fibers in each of those muscles will fire at once [ citation needed ] , though this ratio can be affected by various physiological and psychological factors (including  Golgi tendon organs  and  Renshaw cells ). This 'low' level of contraction is a protective mechanism to prevent  avulsion  of the tendon—the force generated by a 95% contraction of all fibers is sufficient to damage the body. In  multiple fiber summation , if the central nervous system sends a weak signal to contract a muscle, the smaller  motor units , being more excitable than the larger ones, are stimulated first. As the  strength of the signal  increases, more motor units are excited in addition to larger ones, with the largest motor units having as much as 50 times the contractile strength as the smaller ones. As more and larger motor units are activated, the force of muscle contraction becomes progressively stronger. A concept known as the size principle, allows for a gradation of muscle force during weak contraction to occur in small steps, which then become progressively larger when greater amounts of force are required.


Finally, if the frequency of muscle action potentials increases such that the muscle contraction reaches its peak force and plateaus at this level, then the contraction is a  tetanus .


Length-tension relationship relates the strength of an isometric contraction to the length of the muscle at which the contraction occurs. Muscles operate with greatest active tension when close to an ideal length (often their resting length). When stretched or shortened beyond this (whether due to the action of the muscle itself or by an outside force), the maximum active tension generated decreases. [ 31 ]  This decrease is minimal for small deviations, but the tension drops off rapidly as the length deviates further from the ideal. Due to the presence of elastic proteins within a muscle cell (such as  titin ) and extracellular matrix, as the muscle is stretched beyond a given length, there is an entirely passive tension, which opposes lengthening. Combined, there is a strong resistance to lengthening an active muscle far beyond the peak of active tension.


Force–velocity relationship relates the speed at which a muscle changes its length (usually regulated by external forces, such as load or other muscles) to the amount of force that it generates. Force declines in a hyperbolic fashion relative to the isometric force as the shortening velocity increases, eventually reaching zero at some maximum velocity. The reverse holds true for when the muscle is stretched – force increases above isometric maximum, until finally reaching an absolute maximum. This intrinsic property of active muscle tissue plays a role in the active damping of joints that are actuated by simultaneously active opposing muscles. In such cases, the force-velocity profile enhances the force produced by the lengthening muscle at the expense of the shortening muscle. This favoring of whichever muscle returns the joint to equilibrium effectively increases the damping of the joint. Moreover, the strength of the damping increases with muscle force. The motor system can thus actively control joint damping via the simultaneous contraction (co-contraction) of opposing muscle groups. [ 32 ]


Smooth muscles  can be divided into two subgroups:  single-unit  and  multiunit . Single-unit smooth muscle cells can be found in the gut and blood vessels. Because these cells are linked together by gap junctions, they are able to contract as a functional  syncytium . Single-unit smooth muscle cells contract myogenically, which can be modulated by the autonomic nervous system.


Unlike single-unit smooth muscle cells, multiunit smooth muscle cells are found in the muscle of the eye and in the base of hair follicles. Multiunit smooth muscle cells contract by being separately stimulated by nerves of the autonomic nervous system. As such, they allow for fine control and gradual responses, much like  motor unit recruitment  in skeletal muscle.


The contractile activity of smooth muscle cells can be tonic (sustained) or phasic (transient) [ 33 ]  and is influenced by multiple inputs such as spontaneous electrical activity, neural and hormonal inputs, local changes in chemical composition, and stretch. [ 1 ]  This is in contrast to the contractile activity of skeletal muscle cells, which relies on a single neural input. Some types of smooth muscle cells are able to generate their own action potentials spontaneously, which usually occur following a  pacemaker potential  or a  slow wave potential . These action potentials are generated by the influx of extracellular  Ca 2+ , and not  Na + . Like skeletal muscles, cytosolic  Ca 2+  ions are also required for crossbridge cycling in smooth muscle cells.


The two sources for cytosolic  Ca 2+  in smooth muscle cells are the extracellular  Ca 2+  entering through calcium channels and the  Ca 2+  ions that are released from the sarcoplasmic reticulum. The elevation of cytosolic  Ca 2+  results in more  Ca 2+  binding to  calmodulin , which then binds and activates  myosin light-chain kinase . The calcium-calmodulin-myosin light-chain kinase complex phosphorylates myosin on the 20  kilodalton  (kDa) myosin light chains on amino acid residue-serine 19, enabling the molecular interaction of myosin and actin, and initiating contraction and activating the  myosin ATPase .  Unlike skeletal muscle cells, smooth muscle cells lack troponin, even though they contain the thin filament protein tropomyosin and other notable proteins – caldesmon and calponin.  Thus, smooth muscle contractions are initiated by the  Ca 2+ -activated phosphorylation of myosin rather than  Ca 2+  binding to the troponin complex that regulates myosin binding sites on actin like in skeletal and cardiac muscles.


Termination of crossbridge cycling (and leaving the muscle in latch-state) occurs when myosin light chain phosphatase removes the phosphate groups from the myosin heads. Phosphorylation of the 20 kDa myosin light chains correlates well with the shortening velocity of smooth muscle. During this period, there is a rapid burst of energy use as measured by oxygen consumption. Within a few minutes of initiation, the calcium level markedly decreases, the 20 kDa myosin light chains' phosphorylation decreases, and energy use decreases; however, force in tonic smooth muscle is maintained. During contraction of muscle, rapidly cycling crossbridges form between activated actin and phosphorylated myosin, generating force. It is hypothesized that the maintenance of force results from dephosphorylated "latch-bridges" that slowly cycle and maintain force. A number of kinases such as  rho kinase ,  DAPK3 , and  protein kinase C  are believed to participate in the sustained phase of contraction, and  Ca 2+  flux may be significant.


Although smooth muscle contractions are myogenic, the rate and strength of their contractions can be modulated by the  autonomic nervous system .  Postganglionic nerve fibers  of  parasympathetic nervous system  release the neurotransmitter acetylcholine, which binds to  muscarinic acetylcholine receptors  (mAChRs) on smooth muscle cells. These receptors are  metabotropic , or G-protein coupled receptors that initiate a second messenger cascade. Conversely, postganglionic nerve fibers of the  sympathetic nervous system  release the neurotransmitters epinephrine and norepinephrine, which bind to adrenergic receptors that are also metabotropic. The exact effects on the smooth muscle depend on the specific characteristics of the receptor activated—both parasympathetic input and sympathetic input can be either excitatory (contractile) or inhibitory (relaxing).


There are two types of  cardiac muscle  cells: autorhythmic and contractile. Autorhythmic cells do not contract, but instead set the pace of contraction for other cardiac muscle cells, which can be modulated by the autonomic nervous system. In contrast, contractile muscle cells (cardiomyocytes) constitute the majority of the heart muscle and are able to contract.


In both skeletal and cardiac muscle excitation-contraction (E-C) coupling, depolarization conduction and Ca 2+  release processes occur. However, though the proteins involved are similar, they are distinct in structure and regulation. The  dihydropyridine receptors  (DHPRs) are encoded by different genes, and the  ryanodine receptors  (RyRs) are distinct isoforms. Besides, DHPR contacts with  RyR1  (main RyR isoform in skeletal muscle) to regulate Ca 2+  release in skeletal muscle, while the  L-type calcium channel  (DHPR on cardiac myocytes) and  RyR2  (main RyR isoform in cardiac muscle) are not physically coupled in cardiac muscle, but face with each other by a junctional coupling. [ 34 ]


Unlike skeletal muscle, E-C coupling in cardiac muscle is thought to depend primarily on a mechanism called  calcium-induced calcium release , [ 35 ]  which is based on the junctional structure between T-tubule and sarcoplasmic reticulum.  Junctophilin-2  (JPH2) is essential to maintain this structure, as well as the integrity of  T-tubule . [ 36 ] [ 37 ] [ 38 ]  Another protein,  receptor accessory protein 5  (REEP5), functions to keep the normal morphology of junctional SR. [ 39 ]  Defects of junctional coupling can result from deficiencies of either of the two proteins.  During the process of calcium-induced calcium release, RyR2s are activated by a calcium trigger, which is brought about by the flow of Ca 2+  through the L-type calcium channels. After this, cardiac muscle tends to exhibit  diad  structures, rather than  triads .


Excitation-contraction coupling in cardiac muscle cells occurs when an action potential is initiated by pacemaker cells in the  sinoatrial node  or  atrioventricular node  and conducted to all cells in the heart via  gap junctions . The action potential travels along the surface membrane into  T-tubules  (the latter are not seen in all cardiac cell types) and the depolarisation causes extracellular  Ca 2+  to enter the cell via L-type calcium channels and possibly  sodium-calcium exchanger  (NCX) during the early part of the  plateau phase . Although this Ca 2+  influx only count for about 10% of the Ca 2+  needed for activation, it is relatively larger than that of skeletal muscle. This  Ca 2+  influx causes a small local increase in intracellular  Ca 2+ . The increase of intracellular  Ca 2+  is detected by RyR2 in the membrane of the sarcoplasmic reticulum, which releases  Ca 2+  in a  positive feedback  physiological response. This positive feedback is known as  calcium-induced calcium release [ 35 ]  and gives rise to  calcium sparks  ( Ca 2+  sparks [ 40 ] ). The spatial and temporal summation of ~30,000  Ca 2+  sparks gives a cell-wide increase in cytoplasmic calcium concentration. [ 41 ]  The increase in cytosolic calcium following the flow of calcium through the cell membrane and sarcoplasmic reticulum is moderated by  calcium buffers , which bind a large proportion of intracellular calcium.  As a result, a large increase in total calcium leads to a relatively small rise in free  Ca 2+ . [ 42 ]


The cytoplasmic calcium binds to Troponin C, moving the tropomyosin complex off the actin binding site allowing the myosin head to bind to the actin filament. From this point on, the contractile mechanism is essentially the same as for skeletal muscle (above). Briefly, using ATP hydrolysis, the myosin head pulls the actin filament toward the centre of the sarcomere.


Following systole, intracellular calcium is taken up by the  sarco/endoplasmic reticulum ATPase  (SERCA) pump back into the sarcoplasmic reticulum ready for the next cycle to begin. Calcium is also ejected from the cell mainly by the  sodium-calcium exchanger  (NCX) and, to a lesser extent, a plasma membrane  calcium ATPase .  Some calcium is also taken up by the mitochondria. [ 43 ]  An enzyme,  phospholamban , serves as a brake for SERCA. At low heart rates, phospholamban is active and slows down the activity of the ATPase so that  Ca 2+  does not have to leave the cell entirely. At high heart rates, phospholamban is phosphorylated and deactivated thus taking most  Ca 2+  from the cytoplasm back into the sarcoplasmic reticulum.  Once again,  calcium buffers  moderate this fall in  Ca 2+ concentration, permitting a relatively small decrease in free  Ca 2+ concentration in response to a large change in total calcium. The falling  Ca 2+ concentration allows the troponin complex to dissociate from the actin filament thereby ending contraction.  The heart relaxes, allowing the ventricles to fill with blood and begin the cardiac cycle again.


In  annelids  such as  earthworms  and  leeches , circular and longitudinal muscles cells form the body wall of these animals and are responsible for their movement. [ 44 ]  In an earthworm that is moving through a soil, for example, contractions of circular and longitudinal muscles occur reciprocally while the  coelomic fluid  serves as a  hydroskeleton  by maintaining turgidity of the earthworm. [ 45 ]  When the circular muscles in the anterior segments contract, the anterior portion of animal's body begins to constrict radially, which pushes the incompressible coelomic fluid forward and increasing the length of the animal. As a result, the front end of the animal moves forward. As the front end of the earthworm becomes anchored and the circular muscles in the anterior segments become relaxed, a wave of longitudinal muscle contractions passes backwards, which pulls the rest of animal's trailing body forward. [ 44 ] [ 45 ]  These alternating waves of circular and longitudinal contractions is called  peristalsis , which underlies the creeping movement of earthworms.


Invertebrates such as annelids,  mollusks , and  nematodes , possess obliquely striated muscles, which contain bands of thick and thin filaments that are arranged helically rather than transversely, like in vertebrate skeletal or cardiac muscles. [ 46 ]  In  bivalves , the obliquely striated muscles can maintain tension over long periods without using too much energy. Bivalves use these muscles to keep their shells closed.


Advanced insects such as  wasps ,  flies ,  bees , and  beetles  possess  asynchronous muscles  that constitute the flight muscles in these animals. [ 46 ]  These flight muscles are often called  fibrillar muscles  because they contain myofibrils that are thick and conspicuous. [ 47 ]  A remarkable feature of these muscles is that they do not require stimulation for each muscle contraction. Hence, they are called  asynchronous muscles  because the number of contractions in these muscles do not correspond (or synchronize) with the number of action potentials. For example, a wing muscle of a tethered fly may receive action potentials at a frequency of 3 Hz but it is able to beat at a frequency of 120 Hz. [ 46 ]  The high frequency beating is made possible because the muscles are connected to a  resonant  system, which is driven to a natural frequency of vibration.


In 1780,  Luigi Galvani  discovered that the muscles of dead frogs' legs twitched when struck by an electrical spark. [ 49 ]  This was one of the first forays into the study of  bioelectricity , a field that still studies the electrical patterns and signals in tissues such as nerves and muscles.


In 1952, the term excitation–contraction coupling was coined to describe the physiological process of converting an electrical stimulus to a mechanical response. [ 50 ]  This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical response is contraction. Excitation–contraction coupling can be dysregulated in many diseases. Though excitation–contraction coupling has been known for over half a century, it is still an active area of biomedical research. The general scheme is that an action potential arrives to depolarize the cell membrane. By mechanisms specific to the muscle type, this depolarization results in an increase in cytosolic  calcium  that is called a calcium transient. This increase in calcium activates calcium-sensitive contractile proteins that then use  ATP  to cause cell shortening.


The mechanism for muscle contraction evaded scientists for years and requires continued research and updating. [ 51 ]  The sliding filament theory was independently developed by  Andrew F. Huxley  and  Rolf Niedergerke  and by  Hugh Huxley  and  Jean Hanson . Their findings were published as two consecutive papers published in the 22 May 1954 issue of  Nature  under the common theme "Structural Changes in Muscle During Contraction". [ 23 ] [ 24 ]


Muscle contractures  can occur for many reasons, such as  paralysis ,  muscular atrophy , and forms of  muscular dystrophy . Fundamentally, the muscle and its tendons shorten, resulting in reduced flexibility.


Various interventions can slow, stop, or even reverse muscle contractures, ranging from physical therapy to surgery.


Joints are usually immobilized in a shortened position resulting in changes within the joint  connective tissue , and the length of the muscle and associated tendon. Prolonged immobilization facilitates tissue proliferation which impinges on the joint space. [ 1 ]  Maintaining a shortened position for a prolonged period of time leads to: fibrous adhesion formation, loss of  sarcomeres , and a loss of tissue extensibility. [ 1 ]


For example, after a fracture when immobilization is done by casting the limb in plaster of paris, the muscle length shortens because the muscle is not used for a large span of time.


A common cause for having the ankle lose its flexibility in this manner is from having sheets tucked in at the foot of the bed when sleeping. The weight of the sheets keep the feet plantarflexed all night. By not tucking the sheets in at the foot of the bed, or by sleeping with the feet hanging off the bed when in the prone position, is part of correcting this imbalance.


Due to sensory issues, some  autistic  people prefer to  toe walk  instead of their feet making full contact with the ground. Chronic toe walking leads to muscle contracture due to the lack of calf muscles being adequately stretched. Once the muscle contracture has developed, the voluntary toe walking then becomes involuntary. [ 2 ]  If someone has a disability that causes spasticity (such as  cerebral palsy ), they may walk on their toes involuntarily.


If  spasticity  is left untreated, contractures can occur. A loss of muscle tone inhibition ( hypertonia ) causes a muscle to become hyperactive resulting in constant contraction, which reduces an individual’s control of the affected area.  The joint will remain in a flexed state producing similar effects as listed in immobilization.


A muscle imbalance between an  agonist and antagonist muscle  can occur due to a neurological disorder, spinal cord injury, myopathy, and our lifestyle/postural habits. [ 1 ] [ 3 ]  One muscle may be normal while the other is atrophic or hypertrophic; alternately, one muscle may be hypertrophic while the other is atrophic. [ 3 ]  A decrease in muscle tone leads to continuous disuse and eventually muscular atrophy. The constant contraction of the agonist muscle with minimal resistance can result in a contracture. Selective muscle hypertrophy may exacerbate contractures and postural instability. [ 3 ]


For example, in the case of partial paralysis (i.e.  poliomyelitis ) the loss of strength and muscle control tend to be greater in some muscles than in others, leading to an imbalance between the various muscle groups around specific joints.  Case in point: when the muscles which dorsiflex (flex the foot upward) are less functional than the muscles which plantarflex (flex the foot downward) a contracture occurs, giving the foot a progressively downward angle and loss of flexibility.


In the  metabolic myopathies  of  GSD-V  (McArdle disease) and  GSD-VII  (Tarui disease), temporary muscle contractures develop in response to impending muscle damage associated with the  ATP  (energy) deficiency. [ 4 ]  The muscle contracts and fails to relax again, becoming hard or stiff, the muscle may swell up, and although temporary, it is longer lasting and generally more painful than muscle cramps. [ 4 ] [ 5 ]  These contractures are different from cramps, because they are not elicited by the nerve, but by intrinsic mechanisms in the muscle itself and are silent on electromyography. [ 4 ]  This type of transient contracture has also been called pseudomyotonia. [ 6 ] [ 7 ]


In GSD-V and GSD-VII, a cramp or contracture is managed by cessation of the causal activity until pain resolves; however, repeated episodes can accumulate muscle damage  (see below under fibrosis) . [ 4 ]  Unlike stretching of muscle cramps, stretching of a muscle in contracture should be avoided as it may cause further muscle damage by tearing muscle fibres (i.e. resist uncurling the fingers of a "clawed" hand). [ 4 ] [ 5 ]


Some  congenital muscular dystrophies , such as  Bethlem myopathy ,  Ullrich congenital muscular dystrophy , Merosin-deficient congenital muscular dystrophy (MDC1A) or LAMA2-related CMD,  rigid spine syndrome  and LMNA-related congenital muscular dystrophy cause muscle contractures to develop. [ 8 ] [ 9 ]  In  Bethlem myopathy  and  Ullrich congenital muscular dystrophy , mutations in  collagen  VI and XII genes result in deficient or dysfunctional microfibrillar collagen in the extracellular matrix of muscle and other connective tissues. [ 8 ] [ 10 ]  The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis. In Bethlem myopathy 1, contractures presenting in infancy may resolve by age 2 years, but reoccur as the disease progresses, typically by late of the first decade or early teens. [ 8 ]


Congenital myopathy  such as, core myopathies, nemaline myopathies and centronuclear myopathies and so forth can result in muscle contractures of the extremities and spine. [ 11 ]


Following trauma (such as fractures, crush injuries, burns and arterial injuries),  ischemia  (restriction of blood flow) leads to the death of muscle tissue ( necrosis ) and can cause contracture, such as  Volkmann's contracture . [ 12 ]


Adhesions  bind two separate tissues or organs together with fibrotic scar tissue, joining muscle fibres to facia, ligaments, or joints.  Fibrosis  occurs within the same organ, the fibrotic scar tissue within skeletal muscle known as myofibrosis, limits muscle contractibility and stiffens muscles. [ 13 ] [ 14 ] [ 15 ]


Muscle injury (such as a large burn or surgery) can cause muscle contractures as internal scar tissue (adhesions and fibrosis) develops. Repetitive muscle injuries (e.g.  sports injuries , major  muscle strains ) and micro-injuries (e.g.  overuse injuries , minor muscle strains) can also cause this. Adhesions and fibrosis are made of dense fibrous tissue, which are strong and supportive, helping to prevent the injury or micro-injury from reoccurring. However, the fibrotic scar tissue causes the muscle tissue to become stuck together which restricts movement, causing pain, weakness, and limited joint mobility. [ 15 ] [ 16 ] [ 17 ] [ 18 ]


Typically performed by physical therapists, passive stretching is a more beneficial preventative measure and tool to maintain available  range of motion  (ROM) rather than used as a treatment. [ 19 ]  It is very important to continually move the limb throughout its full range at a specific velocity but a passive stretch can’t be maintained for the period of time required for optimal benefit.


A 2017 Cochrane review found that stretching does not provide any short-term pain relief. [ 20 ]


A contracture corrective device (CCD) is a dynamic splint that provides a continuous stretch with a continuous force and operates based on the principles of  creep . [ 1 ]  It is the most advantageous splint but more research is required. Splints are used in long term treatments and must be removed in order to stretch the antagonist muscle to maintain range of motion (passive stretching).


Electrical stimulation  improves passive range of motion but only temporarily. [ 1 ]  Once the treatment is withdrawn, all benefits are reduced.  It can play a critical role in muscle  atrophy  prevention.


Surgery is a solution to muscle shortening but other complications may arise. Following muscle lengthening surgery,  force  production and  ROM  is usually reduced due to the shift in sarcomere locations between a muscle's maximal and minimal length. [ 1 ]  In adjunct with surgery, refractory muscle contracture can also be treated with  Botulinum toxins  A and B; however, the effectiveness of the toxin is slowly lost over time, and most patients need a single treatment to correct muscle contracture over the first few weeks after surgery. [ 21 ]  Shortening of the surgically lengthened muscle can re-occur.


A  muscle fascicle  is a bundle of  skeletal muscle fibers  surrounded by  perimysium , a type of  connective tissue . [ 1 ]


Muscle cells  are grouped into muscle fascicles by enveloping  perimysium   connective tissue . [ 1 ]  Fascicles are bundled together by  epimysium  connective tissue. [ 1 ]  Muscle fascicles typically only contain one type of muscle cell (either  type I fibres  or  type II fibres ), but can contain a mixture of both types. [ 2 ]


In the  heart , specialized  cardiac muscle cells  transmit  electrical impulses  from the  atrioventricular node  (AV node) to the  Purkinje fibers  – fascicles, also referred to as bundle branches. [ citation needed ]  These start as a single fascicle of fibers at the AV node called the  bundle of His  that then splits into three bundle branches: the right fascicular branch, left anterior fascicular branch, and left posterior fascicular branch.


Myositis  may cause  thickening  of the muscle fascicles. [ 3 ]  This may be detected with  ultrasound scans . [ 3 ]


Muscle fascicle structure is a useful diagnostic tool for  dermatomyositis . Myocytes towards the edges of the muscle fascicle are typically narrower, while those at the centre of the muscle fascicle are a normal thickness. [ 4 ]


Muscle fascicles may be involved in  myokymia , although commonly only individual myocytes are involved. [ 5 ]


Muscle hypertrophy  or  muscle building  involves a  hypertrophy  or increase in size of  skeletal muscle  through a growth in size of its component  cells . Two factors contribute to hypertrophy:  sarcoplasmic  hypertrophy, which focuses more on increased muscle  glycogen  storage; and  myofibrillar  hypertrophy, which focuses more on increased myofibril size. [ 1 ]  It is the primary focus of  bodybuilding -related activities.


A range of stimuli can increase the volume of muscle cells. These changes occur as an adaptive response that serves to increase the ability to generate  force  or resist  fatigue  in anaerobic conditions.


Strength training  (resistance training) causes neural and muscular adaptations which increase the capacity of an athlete to exert force through voluntary muscular contraction: After an initial period of neuro-muscular adaptation, the muscle tissue expands by creating  sarcomeres  (contractile elements) and increasing non-contractile elements like  sarcoplasmic  fluid. [ 2 ]


Muscular hypertrophy can be induced by  progressive overload  (a strategy of progressively increasing resistance or repetitions over successive bouts of exercise to maintain a high  level of effort ). [ 3 ]   However, the precise mechanisms are not clearly understood; the current accepted theory is through the combination of mechanical tension, metabolic stress, and muscle damage. Although, there is insufficient evidence to suggest that metabolic stress has any significant effect on hypertrophy outcomes. [ 4 ]


Muscular hypertrophy plays an important role in competitive  bodybuilding  and strength sports like  powerlifting , American football, and  Olympic weightlifting .


The best approach to specifically achieve muscle growth remains controversial (as opposed to focusing on gaining strength, power, or endurance); it was generally considered that consistent anaerobic strength training will produce hypertrophy over the long term, in addition to its effects on muscular strength and endurance. Muscular hypertrophy can be increased through  strength training  and other short-duration, high-intensity  anaerobic exercises . Lower-intensity, longer-duration  aerobic exercise  generally does not result in very effective tissue hypertrophy; instead, endurance athletes enhance storage of fats and  carbohydrates  within the muscles, [ 5 ]  as well as  neovascularization . [ 6 ] [ 7 ]


During a workout, increased blood flow to metabolically active areas causes muscles to temporarily increase in size. This phenomenon is referred to as transient hypertrophy, or more commonly known as being "pumped up" or getting "a pump." [ 8 ]  About two hours after a workout and typically for seven to eleven days, muscles swell due to an inflammation response as tissue damage is repaired. [ 9 ]  Longer-term hypertrophy occurs due to more permanent changes in muscle structure.


Hirono et al. explained the causes of Muscle swelling: [ 10 ]


"Muscle swelling occurs as a result of the following:


(a) resistance exercise can increase  phosphocreatine  and  hydrogen ion  accumulations due to  blood lactate  and  growth hormone  production, and


(b) the high lactate and hydrogen ion concentrations may accelerate water uptake in muscle cells according to  cell permeability  because the molecular weights of the lactate and hydrogen ions are smaller than that of muscle glycogen."


Biological factors (such as  DNA  and sex), nutrition, and training variables can affect muscle hypertrophy. [ 11 ]


Individual differences in genetics account for a substantial portion of the variance in existing muscle mass. A classical twin study design (similar to those of behavioral genetics) estimated that about 53% of the variance in lean body mass is heritable, [ 12 ]  along with about 45% of the variance in muscle fiber proportion. [ 13 ]


During puberty in males, hypertrophy occurs at an increased rate. Natural hypertrophy normally stops at full growth in the late teens. As  testosterone  is one of the body's major growth hormones, on average, males find hypertrophy much easier (on an absolute scale) to achieve than females, and, on average, have about 60% more muscle mass than women. [ 14 ]  Taking additional testosterone, as in  anabolic steroids , will increase results. It is also considered a  performance-enhancing drug , the use of which can cause competitors to be suspended or banned from competitions. Testosterone is also a medically regulated substance in most [ 15 ] [ 16 ]  countries, making it illegal to possess without a  medical prescription . Anabolic steroid use can cause  testicular atrophy , cardiac arrest, [ 17 ]  and  gynecomastia . [ 18 ]


In the long term, a positive energy balance, when more calories are consumed rather than burned, is helpful for  anabolism  and therefore muscle hypertrophy. An increased requirement for protein can help elevate protein synthesis, which is seen in athletes training for muscle hypertrophy. However, there is no scientific consensus on whether strength-training athletes have increased protein requirements. [ 19 ]


Training variables, in the context of strength training, such as frequency, intensity, and total volume also directly affect the increase of muscle hypertrophy. A gradual increase in all of these training variables will yield muscular hypertrophy. [ 20 ]


The message filters down to alter the pattern of  gene expression . The additional contractile proteins appear to be incorporated into existing myofibrils (the chains of  sarcomeres  within a muscle cell). There appears to be some limit to how large a myofibril can become: at some point, they split. These events appear to occur within each muscle fiber. That is hypertrophy results primarily from the growth of each muscle cell rather than an increase in the number of cells.  Skeletal muscle  cells are however unique in the body in that they can contain multiple nuclei, and the number of nuclei can increase. [ 21 ]


Cortisol  decreases amino acid uptake by muscle tissue, and inhibits protein synthesis. [ 22 ]  The short-term increase in protein synthesis that occurs subsequent to resistance training returns to normal after approximately 28 hours in adequately fed male youths. [ 23 ]  Another study determined that muscle protein synthesis was elevated even 72 hours following training. [ 24 ]


A small study performed on young and elderly found that ingestion of 340 grams of lean beef (90 g protein) did not increase muscle protein synthesis any more than ingestion of 113 grams of lean beef (30 g protein). In both groups, muscle protein synthesis increased by 50%. The study concluded that more than 30 g protein in a single meal did not further enhance the stimulation of muscle protein synthesis in young and elderly. [ 25 ]  However, this study didn't check protein synthesis in relation to training; therefore conclusions from this research are controversial. A 2018 review of the scientific literature [ 26 ]  concluded that for the purpose of building lean muscle tissue, a minimum of 1.6 g protein per kilogram of body weight is required, which can for example be divided over 4 meals or snacks and spread out over the day. [ citation needed ]


It is not uncommon for bodybuilders to advise a protein intake as high as 2–4 g per kilogram of bodyweight per day. [ 27 ]  However, scientific literature has suggested this is higher than necessary, as protein intakes greater than 1.8 g per kilogram of body weight showed to have no greater effect on muscle hypertrophy. [ 28 ]  A study carried out by American College of Sports Medicine (2002) put the recommended daily protein intake for athletes at 1.2–1.8 g per kilogram of body weight. [ 28 ] [ 29 ] [ 30 ]  Conversely,  Di Pasquale  (2008), citing recent studies, recommends a minimum protein intake of 2.2 g/kg "for anyone involved in competitive or intense recreational sports who wants to maximize lean body mass but does not wish to gain weight. However athletes involved in strength events (..) may need even more to maximize body composition and athletic performance. In those attempting to minimize body fat and thus maximize body composition, for example in sports with weight classes and in bodybuilding, it's possible that protein may well make up over 50% of their daily caloric intake." [ 31 ]


Microtrauma is tiny damage to the muscle fibers. The precise relation between microtrauma and muscle growth is not entirely understood yet. [ citation needed ]


One theory is that microtrauma plays a significant role in muscle growth. [ 32 ] [ 33 ]  When microtrauma occurs (from weight training or other strenuous activities), the body responds by overcompensating, replacing the damaged tissue and adding more, so that the risk of repeat damage is reduced. Damage to these fibers has been theorized as the possible cause for the symptoms of  delayed onset muscle soreness  (DOMS), and is why progressive overload is essential to continued improvement, as the body adapts and becomes more resistant to stress.


However, other work examining the time course of changes in muscle protein synthesis and their relationship to hypertrophy showed that damage was unrelated to hypertrophy. [ 34 ]  In fact, in one study [ 34 ]  the authors showed that it was not until the damage subsided that protein synthesis was directed to muscle growth.


In the bodybuilding and fitness community and even in some academic books skeletal muscle hypertrophy is described as being in one of two types: Sarcoplasmic or myofibrillar. [ qualify evidence ]  According to this hypothesis, during sarcoplasmic hypertrophy, the volume of  sarcoplasmic  fluid in the muscle cell increases with no accompanying increase in muscular strength, whereas during myofibrillar hypertrophy,  actin  and  myosin  contractile proteins increase in number and add to muscular strength as well as a small increase in the size of the muscle. Sarcoplasmic hypertrophy is greater in the muscles of  bodybuilders  because studies suggest sarcoplasmic hypertrophy shows a greater increase in muscle size while myofibrillar hypertrophy proves to increase overall muscular strength making it more dominant in  Olympic weightlifters . [ 35 ]  These two forms of adaptations rarely occur completely independently of one another; one can experience a large increase in fluid with a slight increase in proteins, a large increase in proteins with a small increase in fluid, or a relatively balanced combination of the two.


Examples of increased muscle hypertrophy are seen in various professional sports, mainly strength related sports such as  boxing ,  olympic weightlifting ,  mixed martial arts ,  rugby ,  professional wrestling  and various forms of gymnastics. Athletes in other more skill-based sports such as basketball, baseball,  ice hockey , and football may also train for increased muscle hypertrophy to better suit their position of play. For example, a  center (basketball)  may want to be bigger and more muscular to better overpower their opponents in the low post. [ 36 ]  Athletes training for these sports train extensively not only in  strength  but also in  cardiovascular  and  muscular endurance  training. [ citation needed ]


Some neuromuscular diseases result in true hypertrophy of one or more skeletal muscles, confirmed by MRI or muscle biopsy. As this muscle hypertrophy is not the result of resistance training nor heavy manual labour, this is why the muscle hypertrophy is described as a  pseudoathletic appearance .


As muscle hypertrophy is a response to strenuous anaerobic activity, ordinary everyday activity would become strenuous in diseases that result in premature  muscle fatigue  (neural or metabolic), or disrupt the  excitation-contraction  coupling in muscle, or cause repetitive or sustained involuntary muscle contractions ( fasciculations ,  myotonia , or  spasticity ). [ 37 ] [ 38 ]  In  lipodystrophy , an abnormal deficit of subcutaneous fat accentuates the appearance of the muscles, though the muscles are quantifiably hypertrophic (possibly due to a metabolic abnormality). [ 39 ] [ 40 ]


Diseases that result in true muscle hypertrophy include, but not limited to, select: muscular dystrophies, metabolic myopathies, endocrine myopathies, congenital myopathies, non-dystrophic myotonias and pseudomyotonias, denervation, spasticity, and lipodystrophy. The muscle hypertrophy may persist throughout the course of the disease, or may later atrophy, or become pseudohypertrophic (muscle atrophy with infiltration of fat or other tissue). For instance, Duchenne and Becker muscular dystrophy may start as true muscle hypertrophy, but later develop into pseudohypertrophy. [ 41 ]


Muscle memory  in  strength training  and  weight-lifting  is the effect that trained athletes experience a rapid return of  muscle mass  and strength after long periods of inactivity. [ 1 ]


The mechanisms implied for the muscle memory suggest that it is mainly related to strength training, and a 2016 study conducted at  Karolinska Institutet  in  Stockholm ,  Sweden  failed to find a memory effect of endurance training. [ 2 ]


Until recently such effects were attributed solely to  muscle memory  in  motor learning  occurring in the central nervous system. Long-term effects of previous training on the muscle fibers themselves, however, have recently also been observed related to  strength training . [ 3 ]


Until recently it was generally assumed that the effects of exercise on muscle was reversible, and that after a long period of de-training the muscle fibers returned to their previous state. For strength training this view was challenged in 2010 by using  in vivo   imaging  techniques revealing specific long lasting structural changes in muscle fibers after a strength-training episode. [ 3 ]


The notion of a memory mechanism residing in  muscle fibers  might have implications for health related exercise advice, and for exclusion times after  doping offences . [ citation needed ]


Muscle memory is probably related to the  cell nuclei  residing inside the muscle fibers. [ citation needed ]


The  muscle cells  are the largest cells in the body with a volume thousands of times larger than most other body cells. [ 4 ]  To support this large volume, the muscle cells are one of the very few in the mammalian body that contain several cell nuclei. Such multinucleated cells are called  syncytia . Strength-training increases muscle mass and force mainly by changing the caliber of each fiber rather than increasing the number of fibers. During such fiber enlargement muscle  stem cells  in the muscle tissue multiply and fuse with pre-existing fibers as to support the larger cellular volume. It has often been assumed that each nucleus can support a certain volume of  cytoplasm , and hence that there is a constant volume domain served by each nucleus, although recent evidence suggests that this is an oversimplification. Until 2008 it was believed that during  muscle wasting , muscle cells lost nuclei by a nuclear self-destruct mechanism called  apoptosis , but observations using time lapse in vivo imaging in mice do not support this model. Direct observation indicated that no nuclei are lost under such conditions, [ 5 ]  and the  apoptosis  observed in the muscle tissue were demonstrated to occur only in other cell nuclei in the tissue, e.g.  connective tissue  and muscle stem cells called  satellite cells . Since in vivo imaging has confirmed that cell nuclei are added during strength training and not lost upon subsequent detraining, [ 3 ]  the nuclei might provide a mechanism for muscle memory. Thus, upon retraining the extra nuclei are already there and can rapidly start synthesizing new proteins to build muscle mass and strength.


The extra muscle nuclei obtained by a strength training episode seems to be very long lasting, perhaps permanent, even in muscles that are inactive for a long time. [ 3 ]  The ability to recruit new nuclei is impaired in the elderly, [ 6 ]  so it might be beneficial to strength train before  senescence .


Doping with  anabolic steroids  also seem to act partly by recruiting new nuclei. [ 7 ] [ 8 ]  It was recently shown in mice [ 9 ]  that a brief exposure to anabolic steroids recruited new muscle nuclei. When the steroids were withdrawn, the muscle rapidly shrank to normal size, but the extra nuclei remained. After a waiting period of 3 months (about 15% of the mouse lifespan), overload exercise led to a muscle growth of 36% within 6 days in the steroid-exposed group, while control muscles that had never been exposed to steroids grew only insignificantly. Since nuclei are long lasting structures in muscle, this suggests that anabolic steroids might have long lasting if not permanent effects on the ability to grow muscle mass. [ 10 ]


Recent evidence has pointed towards epigenetics as a plausible mechanism by which muscle may remember an initial bout of resistance/strength training. Indeed, via the retention of hypomethylated modifications to DNA, a recent study identified an enhanced morphological adaptation to a 7 week bout of resistance exercise, following an initial 7 week training phase and detraining phase. [ 11 ] [ 12 ]


In  physiology , medicine, and  anatomy ,  muscle tone  ( residual muscle tension  or  tonus ) is the continuous and passive partial  contraction of the muscles , or the muscle's resistance to passive stretch during resting state. [ 1 ] [ 2 ]  It helps to maintain  posture  and declines during  REM sleep . [ 3 ]  Muscle tone is regulated by the activity of the  motor neurons  and can be affected by various factors, including age, disease, and nerve damage.


If a sudden  pull  or stretch occurs, the body responds by automatically increasing the muscle's tension, a reflex which helps guard against danger as well as helping maintain  balance .  Such near-continuous  innervation  can be thought of as a "default" or "steady state" condition for muscles. Both the  extensor  and  flexor  muscles are involved in the maintenance of a constant tone while at rest. In skeletal muscles, this helps maintain a normal posture.


Resting muscle tone varies along a  bell-shaped curve .  Low tone is perceived as "lax, flabby, floppy, mushy, dead weight" and high tone is perceived as "tight, light, strong".  Muscles with high tone are not necessarily strong and muscles with low tone are not necessarily weak.  In general, low tone does increase flexibility and decrease strength, and high tone does decrease flexibility and increase strength, but with many exceptions.  A person with low tone will most likely not be able to engage in "explosive" movement such as needed in a sprinter or high jumper.  These athletes usually have high tone that is within normal limits. A person with high tone will usually not be flexible in activities such as dance and yoga.  Joint laxity contributes greatly to flexibility, especially with flexibility in one or a few areas, instead of overall flexibility.


For example, a person can be high tone with normal to poor flexibility in most areas, but be able to put the palms of the hands on the floor with straight knees due to hypermobile sacroiliac joints. [ citation needed ]  It is important to assess several areas before deciding if a person has high, low, or normal muscle tone.  A fairly reliable assessment item is how the person feels when picked up. [ citation needed ]   For example, small children with low tone can feel heavy while larger, high tone children feel light, which corresponds with the description of "dead weight". [ citation needed ]


Physical disorders can result in abnormally low ( hypotonia ) or high ( hypertonia ) muscle tone. [ 4 ]  Another form of hypertonia is  paratonia , which is associated with  dementia . [ 5 ]  Hypotonia is seen in lower motor neuron disease like  poliomyelitis . Hypotonia can present clinically as muscle  flaccidity , where the limbs appear floppy,  stretch reflex  responses are decreased, and the limb's resistance to passive movement is also decreased. [ 1 ]  Hypertonia is seen in upper motor neuron diseases like lesions in pyramidal tract and extrapyramidal tract. Hypertonia can present clinically as either  spasticity  or  rigidity . While  spasticity  is velocity-dependent resistance to passive stretch (e.g., passively moving an elbow quickly will elicit increased muscle tone, but passively moving elbow slowly may not elicit increased muscle tone),  rigidity  is velocity-independent resistance to passive stretch (i.e. there is uniform increased tone whether the elbow is passively moved quickly or slowly). [ 1 ]
 Spasticity  can be in the form of the  clasp-knife response , in which there is increased resistance only at the beginning or at the end of the movement. Rigidity can be of the leadpipe type, in which there is resistance throughout to passive movement, or it may be of cogwheel type, in which the resistance to passive movement is in a jerky manner.


In  ophthalmology , tonus may be a central consideration in  eye surgery , as in the manipulation of  extraocular muscles  to repair  strabismus . Tonicity aberrations are associated with many diseases of the eye (e.g.  Adie syndrome ). [ citation needed ]


Normally, people are unaware of their muscle tone in their daily activities. The body maintains the balance between the tone of flexor and extensor muscle groups. Sometimes, in normal, healthy people, that tone is lost either in flexors or extensor muscle groups in isolation, temporarily and intermittently resulting in  muscle cramps . Treating these extensor or flexor group of muscles in isolation can be difficult. Generally,  muscle relaxants  or  quinine  can help with cramps and is warranted when they become troublesome. But these medication cause their relaxing effect in both groups by moderating their tone. The cause of disproportionate intermittent contractions of either flexors or extensors or the cause of cramps is unknown. The stimulus for muscle cramps may originate in the cerebral cortex, the spinal cord, or the muscle itself. This could indicate developing pathology or other problems in the future.


In  human anatomy , the  muscles of the hip joint  are those  muscles  that cause movement in the  hip . Most modern anatomists define 17 of these muscles, although some additional muscles may sometimes be considered. These are often divided into four groups according to their orientation around the hip joint: the  gluteal group ; the  lateral rotator group ; the  adductor group ; and the  iliopsoas group .


The muscles of the hip consist of four main groups


The gluteal muscles include the  gluteus maximus ,  gluteus medius ,  gluteus minimus , and  tensor fasciae latae . They cover the lateral surface of the  ilium . The gluteus maximus, which forms most of the muscle of the  buttocks , originates primarily on the ilium and  sacrum  and inserts on the  gluteal tuberosity  of the  femur  as well as the  iliotibial tract , a tract of strong  fibrous tissue  that runs along the lateral  thigh  to the  tibia  and  fibula . The gluteus medius and gluteus minimus originate anterior to the gluteus maximus on the ilium and both insert on the  greater trochanter  of the femur. The tensor fasciae latae shares its origin with the gluteus maximus at the ilium and also shares the insertion at the iliotibial tract.


The  adductor brevis ,  adductor longus ,  adductor magnus ,  pectineus , and  gracilis  make up the adductor group. The adductors all originate on the  pubis  and insert on the medial, posterior surface of the femur, with the exception of the gracilis which inserts just below the  medial condyle  of the tibia.


The  iliacus  and  psoas major  comprise the iliopsoas group. The psoas major is a large muscle that runs from the bodies and disc of the L1 to L5  vertebrae , joins with the iliacus via its  tendon , and connects to the  lesser trochanter  of the femur. The iliacus originates on the  iliac fossa  of the ilium. Together these muscles are commonly referred to as the "iliopsoas".


This group consists of the  externus  and  internus obturators , the  piriformis , the  superior  and  inferior gemelli , and the  quadratus femoris . These six originate at or below the  acetabulum  of the ilium and insert on or near the greater trochanter of the femur.


Additional muscles, such as the  rectus femoris  and the  sartorius , can cause some movement in the hip joint. However these muscles primarily move the  knee , and are not generally classified as muscles of the hip.


The  hamstring  muscles, which originate mostly from the  ischial tuberosity  inserting on the tibia/fibula, have a large  moment  assisting with hip extension.


Movements of the hip occur because multiple muscles activate at once. Most muscles are also responsible for more than one type of movement.


Movements of the hip are described in  anatomical terminology  using  anatomical terms of motion . The movement that brings the thighs close to the abdomen is called "flexion". When the legs open, such as in the  lotus posture  of  yoga , this is called "lateral rotation", with the opposite movement called "medial rotation". Hip  abduction  occurs when the femur moves outward to the side, as in taking the thighs apart. Hip  adduction  occurs when the femur moves back to the midline. Many muscles contribute to these movements:


Hip muscles also play a role in maintaining the standing posture. These muscles work in an integrated system with muscles of the shoulder, neck, core, lower leg, and supporting muscles of the spine, to provide the ability to stand with good posture. [ 1 ]  These muscles include the  gluteus medius  and  gluteus minimus  which abduct the thigh, prevent swaying of hips, stabilize pelvic region while keeping hips level, and shift an individual's weight in order to adjust body placement to increase one's overall body stability. [ 2 ]


The  muscular lacuna  (Latin:  lacuna musculorum ) is the lateral compartment of the thigh beneath the  inguinal ligament . It is separated from the medial  vascular lacuna  by the  iliopectineal arch . It is occupied/traversed by the  iliopsoas muscle , and  femoral nerve . [ 1 ]  The  lateral cutaneous nerve of the thigh  may pass through the muscular lacuna, [ 2 ]  or it may pierce the inguinal ligament itself. [ 3 ]


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Myogenesis  is the formation of  skeletal muscular tissue , particularly during  embryonic development .


Muscle fibers  generally form through the fusion of  precursor   myoblasts  into  multinucleated  fibers called  myotubes . In the early development of an  embryo , myoblasts can either  proliferate , or  differentiate  into a myotube.  What controls this choice in vivo is generally unclear. If placed in cell culture, most myoblasts will proliferate if enough  fibroblast growth factor  (FGF) or another growth factor is present in the medium surrounding the cells. When the growth factor runs out, the myoblasts cease division and undergo terminal differentiation into myotubes.  Myoblast differentiation proceeds in stages.  The first stage involves cell cycle exit and the commencement of expression of certain genes.


The second stage of differentiation involves the alignment of the myoblasts with one another. Studies have shown that even rat and chick myoblasts can recognise and align with one another, suggesting evolutionary conservation of the mechanisms involved. [ 1 ]


The third stage is the actual  cell fusion  itself. In this stage, the presence of  calcium  ions is critical. Fusion in humans is aided by a set of  metalloproteinases  coded for by the  ADAM12   gene , and a variety of other proteins. Fusion involves recruitment of  actin  to the  plasma membrane , followed by close apposition and creation of a pore that subsequently rapidly widens.


Novel genes and their protein products that are expressed during the process are under active investigation in many laboratories.  They include:


There are a number of stages (listed below) of muscle development, or myogenesis. [ 4 ]  Each stage has various associated genetic factors lack of which will result in muscular defects.


Associated Genetic Factors:   PAX3  and  c-Met
Mutations in PAX3 can cause a failure in c-Met expression. Such a mutation would result in a lack of lateral migration.


PAX3 mediates the transcription of c-Met and is responsible for the activation of MyoD expression—one of the functions of MyoD is to promote the regenerative ability of  satellite cells  (described below). [ 4 ]  PAX3 is generally expressed at its highest levels during  embryonic development  and is expressed at a lesser degree during the fetal stages; it is expressed in migrating hypaxial cells and dermomyotome cells, but is not expressed at all during the development of  facial muscle . [ 4 ]  Mutations in Pax3 can cause a variety of complications including  Waardenburg syndrome  I and III as well as  craniofacial-deafness-hand syndrome . [ 4 ]  Waardenburg syndrome is most often associated with congenital disorders involving the intestinal tract and spine, an elevation of the scapula, among other symptoms. Each stage has various associated genetic factors without which will result in muscular defects. [ 4 ]


Associated Genetic Factors:   c-Met / HGF  and  LBX1
Mutations in these genetic factors causes a lack of migration.


LBX1 is responsible for the development and organization of muscles in the dorsal forelimb as well as the movement of dorsal muscles into the limb following  delamination . [ 4 ]  Without LBX1, limb muscles will fail to form properly; studies have shown that hindlimb muscles are severely affected by this deletion while only flexor muscles form in the forelimb muscles as a result of ventral muscle migration. [ 4 ]


c-Met is a  tyrosine kinase receptor  that is required for the survival and proliferation of migrating myoblasts. A lack of c-Met disrupts secondary myogenesis and—as in LBX1—prevents the formation of limb musculature. [ 4 ]  It is clear that c-Met plays an important role in delamination and proliferation in addition to migration. PAX3 is needed for the transcription of c-Met. [ 4 ]


Associated Genetic Factors:   PAX3 ,  c-Met ,  Mox2 ,  MSX1 , Six,  Myf5 , and  MyoD


Mox2 (also referred to as MEOX-2) plays an important role in the induction of  mesoderm  and  regional specification . [ 4 ]  Impairing the function of Mox2 will prevent the proliferation of  myogenic precursors  and will cause abnormal patterning of limb muscles. [ 5 ]  Specifically, studies have shown that hindlimbs are severely reduced in size while specific forelimb muscles will fail to form. [ 4 ]


Myf5 is required for proper myoblast proliferation. [ 4 ]  Studies have shown that mice muscle development in the intercostal and paraspinal regions can be delayed by inactivating Myf-5. [ 4 ]  Myf5 is considered to be the earliest expressed regulatory factor gene in myogenesis. If Myf-5 and MyoD are both inactivated, there will be a complete absence of skeletal muscle. [ 4 ]  These consequences further reveal the complexity of myogenesis and the importance of each genetic factor in proper muscle development.


Associated Genetic Factors:   Myf5  and  MyoD
One of the most important stages in myogenesis determination requires both Myf5 and MyoD to function properly in order for myogenic cells to progress normally. Mutations in either associated genetic factor will cause the cells to adopt non-muscular phenotypes. [ 4 ]


As stated earlier, the combination of Myf5 and MyoD is crucial to the success of myogenesis. Both MyoD and Myf5 are members of the myogenic bHLH (basic helix-loop-helix) proteins transcription factor family. [ 6 ]  Cells that make myogenic  bHLH transcription factors  (including MyoD or Myf5) are committed to development as a muscle cell. [ 7 ]  Consequently, the simultaneous deletion of Myf5 and MyoD also results in a complete lack of  skeletal muscle  formation. [ 7 ]  Research has shown that MyoD directly activates its own gene; this means that the protein made binds the  myoD  gene and continues a cycle of MyoD protein production. [ 7 ]  Meanwhile, Myf5 expression is regulated by  Sonic hedgehog ,  Wnt1 , and MyoD itself. [ 4 ]  By noting the role of MyoD in regulating Myf5, the crucial interconnectedness of the two genetic factors becomes clear. [ 4 ]


Associated genetic factors:   Myogenin ,  Mcf2 , Six,  MyoD , and  Myf6
Mutations in these associated genetic factors will prevent myocytes from advancing and maturing.


Myogenin  (also known as Myf4) is required for the fusion of myogenic precursor cells to either new or previously existing fibers. [ 4 ]  In general, myogenin is associated with amplifying expression of genes that are already being expressed in the organism. Deleting myogenin results in nearly complete loss of differentiated muscle fibers and severe loss of skeletal muscle mass in the lateral/ventral body wall. [ 4 ]


Myf-6 (also known as  MRF4  or Herculin) is important to myotube differentiation and is specific to skeletal muscle. [ 4 ]  Mutations in Myf-6 can provoke disorders including  centronuclear myopathy  and  Becker muscular dystrophy . [ 4 ]


Associated genetic factors:   LBX1  and  Mox2
In specific muscle formation, mutations in associated genetic factors begin to affect specific muscular regions. Because of its large responsibility in the movement of dorsal muscles into the limb following delamination, mutation or deletion of Lbx1 results in defects in extensor and hindlimb muscles. [ 4 ]  As stated in the Proliferation section, Mox2 deletion or mutation causes abnormal patterning of limb muscles. The consequences of this abnormal patterning include severe reduction in size of hindlimbs and complete absence of forelimb muscles. [ 4 ]


Associated genetic factors:   PAX7
Mutations in Pax7 will prevent the formation of satellite cells and, in turn, prevent postnatal muscle growth. [ 4 ]


Satellite cells  are described as quiescent myoblasts and neighbor muscle fiber  sarcolemma . [ 4 ]  They are crucial for the repair of muscle, but have a very limited ability to replicate. Activated by stimuli such as injury or high mechanical load, satellite cells are required for  muscle regeneration  in adult organisms. [ 4 ]  In addition, satellite cells have the capability to also differentiate into bone or fat. In this way, satellite cells have an important role in not only muscle development, but in the maintenance of muscle through adulthood. [ 4 ]


During  embryogenesis , the  dermomyotome  and/or  myotome  in the  somites  contain the myogenic progenitor cells that will evolve into the prospective skeletal muscle. [ 8 ]   The determination of dermomyotome and myotome is regulated by a gene regulatory network that includes a member of the  T-box  family, tbx6, ripply1, and mesp-ba. [ 9 ]    Skeletal myogenesis depends on the strict regulation of various gene subsets in order to differentiate the myogenic progenitors into myofibers.  Basic helix-loop-helix (bHLH) transcription factors, MyoD, Myf5, myogenin, and MRF4 are critical to its formation. MyoD and Myf5 enable the differentiation of myogenic progenitors into myoblasts, followed by myogenin, which differentiates the myoblast into myotubes. [ 8 ]  MRF4 is important for blocking the transcription of muscle-specific promoters, enabling skeletal muscle progenitors to grow and proliferate before differentiating.


There are a number of events that occur in order to propel the specification of muscle cells in the somite. For both the lateral and medial regions of the somite,  paracrine  factors induce myotome cells to produce MyoD protein—thereby causing them to develop as muscle cells. [ 10 ]  A transcription factor ( TCF4 ) of connective tissue  fibroblasts  is involved in the regulation of myogenesis. Specifically, it regulates the type of muscle fiber developed and its maturations. [ 4 ]  Low levels of TCF4 promote both slow and fast myogenesis, overall promoting the maturation of muscle fiber type. Thereby this shows the close relationship of muscle with connective tissue during the embryonic development. [ 11 ]


Regulation of myogenic differentiation is controlled by two pathways: the  phosphatidylinositol 3-kinase /Akt pathway and the  Notch /Hes pathway, which work in a collaborative manner to suppress MyoD transcription. [ 6 ]  The O subfamily of the forkhead proteins ( FOXO ) play a critical role in regulation of myogenic differentiation as they stabilize Notch/Hes binding. Research has shown that knockout of FOXO1 in mice increases MyoD expression, altering the distribution of  fast-twitch  and slow-twitch fibers. [ 6 ]


Primary muscle fibers originate from  primary myoblasts  and tend to develop into slow muscle fibers. [ 4 ]  Secondary muscle fibers then form around the primary fibers near the time of innervation. These muscle fibers form from secondary myoblasts and usually develop as fast muscle fibers. Finally, the muscle fibers that form later arise from satellite cells. [ 4 ]


Two genes significant in muscle fusion are  Mef2  and the  twist transcription factor .  Studies have shown knockouts for Mef2C in mice lead to muscle defects in cardiac and smooth muscle development, particularly in fusion. [ 12 ]   The twist gene plays a role in muscle differentiation.


The  SIX1  gene plays a critical role in  hypaxial muscle  differentiation in myogenesis. In mice lacking this gene, severe muscle  hypoplasia  affected most of the body muscles, specifically hypaxial muscles. [ 13 ]


In myoblasts, PtdIns5P, produced by the lipid phosphatase MTM1, is rapidly metabolized by PI5P 4-kinase α into PI(4,5)P2, which accumulates at the plasma membrane. This accumulation facilitates the formation of podosome-like protrusions, where the fusogen Myomaker is localized, playing a crucial role in the spatiotemporal regulation of myoblast fusion. [ 14 ]


There are 3 types of proteins produced during myogenesis. [ 5 ]   Class A proteins are the most abundant and are synthesized continuously throughout myogenesis.  Class B proteins are proteins that are initiated during myogenesis and continued throughout development.  Class C proteins are those synthesized at specific times during development.  Also 3 different forms of  actin  were identified during myogenesis.


Sim2 , a  BHLH-Pas transcription factor , inhibits transcription by active repression and displays enhanced expression in ventral limb muscle masses during chick and mouse embryonic development.  It accomplishes this by repressing MyoD transcription by binding to the enhancer region, and prevents premature myogenesis. [ 15 ]


Delta1  expression in  neural crest cells  is necessary for muscle differentiation of the  somites , through the  Notch signaling pathway .  Gain and loss of this ligand in  neural crest cells  results in delayed or premature myogenesis. [ 16 ]


The significance of  alternative splicing  was elucidated using  microarrary analysis  of differentiating  C2C12  myoblasts. [ 17 ]  95 alternative splicing events occur during  C2C12  differentiation in myogenesis. Therefore,  alternative splicing  is necessary in myogenesis.


Systems approach is a method used to study myogenesis, which manipulates a number of different techniques like  high-throughput screening  technologies, genome wide cell-based  assays , and  bioinformatics , to identify different factors of a system. [ 8 ]  This has been specifically used in the investigation of skeletal muscle development and the identification of its regulatory network.


Systems approach  using  high-throughput sequencing  and  ChIP-chip  analysis has been essential in elucidating the targets of myogenic regulatory factors like MyoD and myogenin, their inter-related targets, and how MyoD acts to alter the epigenome in myoblasts and myotubes. [ 8 ]  This has also revealed the significance of PAX3 in myogenesis, and that it ensures the survival of myogenic progenitors. [ 8 ]


This approach, using cell based high-throughput transfection assay and whole-mount  in situ hybridization , was used in identifying the myogenetic regulator RP58, and the tendon differentiation gene, Mohawk homeobox. [ 8 ]


Myomeres  are blocks of skeletal muscle tissue arranged in sequence, commonly found in  aquatic   chordates . Myomeres are separated from adjacent myomeres by  connective   fascia  (myosepta) and most easily seen in  larval   fishes  or in the  olm . Myomere counts are sometimes used for identifying specimens, since their number corresponds to the number of vertebrae in the adults. Location varies, with some species containing these only near the tails, while some have them located near the scapular or pelvic girdles. Depending on the species, myomeres could be arranged in an epaxial or hypaxial manner. Hypaxial refers to ventral muscles and related structures while epaxial refers to more dorsal muscles. The horizontal septum divides these two regions in vertebrates from cyclostomes to gnathostomes. In  terrestrial chordates , the myomeres become fused as well as indistinct, due to the disappearance of myosepta.


The shape of myomeres varies by species. Myomeres are commonly zig-zag, "V" (lancelets), "W" (fishes), or straight (tetrapods)– shaped muscle fibers. Generally, cyclostome myomeres are arranged in vertical strips while those of jawed fishes are folded in a complex matter due to swimming capability evolution. Specifically, myomeres of elasmobranchs and eels are W-shaped. Contrastingly, myomeres of tetrapods run vertically and do not display complex folding. Another species with simply-lain myomeres are mudpuppies. Myomeres overlap each other in succession, meaning myomere activation also allows neighboring myomeres to activate. [ 1 ]


Myomeres are made up of myoglobin-rich dark muscle as well as white muscle. Dark muscle, generally, functions as slow-twitch muscle fibers while white muscle is composed of fast-twitch fibers.


Specifically, three types of myomeres in fish-like chordates include amphioxine (lancelet), cyclostomine (jawless fish), and gnathostomine (jawed fish). A common function shared by all of these is that they function to flex the body laterally into concavity to provide force for locomotion. [ 1 ]


Since myomeres are composed of multinucleated myofibers (contractile cells), force can be generated via muscle contraction that gets transmitted by the intricate connective tissue (myosepta) network.


The folded shape of each myomere as V- or W-shaped extends over various axial segments, allowing fibers control over a large amount of the body. Specifically, myomeres are overlapping cones bound by connective tissue. Myomeres compose most of the lateral musculature and provide propulsive force to travel along the line of travel. In this sense, they cause flexion to either side in order to produce locomotor force. Myomeres attach to centra of vertebrae, and neural and haemal spines.


Further, myomeres of fish are divided by a horizontal septum into dorsal (epaxial) and ventral (hypaxial) sections as mentioned in previous paragraphs. Further, spinal nerves pass into each myomere. [ 2 ]


There are different variations of myomere activation depending on the type of swimming or movement. For example, high loading situations such as fast-starts and turning require almost maximal myomere activation in teleost fish. Further, if swim speeds are lower and movement is in one plane, there is less activation of myomeres. Further, research has discovered that fish are able to spatially restrict axial myomeres during different swimming behaviors. [ 3 ] [ 4 ]


Some research theorizes that myomeres play additional roles in for the fish beyond force generation for swimming. For example, this microdissection and polarized light microscopy research suggests that anterior myomeres have elongated and reinforced dorsal posterior cones that allow epaxial muscle force to be transmitted to the neurocranium for elevation during suction feeding.


Published information on  Pikaia gracilens  (a well-known  Cambrian fossil ) explains evolution of swimming ability in chordates related to myomere shape and function. Specifically, myomeres in this species possessed minimal overlap between successive ones and myosepta dividing them were gently curved. In a biomechanical evaluation, it is presumed that  Pikaia  were not capable of rapid swimming like in living chordates. Several theories for this idea include lacking fast-twitch muscle fibers, ancestral muscle fiber types more like modern slow-twitch fibers, and less tension on myosepta due to less overlap between successive myomeres. [ 5 ]


Larval fish and  amphioxus  myomeres are V-shaped. They are involved in the specialized notochord of amphioxus. There are muscle cells within myomeres that send, and synapse cytoplasmic extensions of muscle cells with contractile fibrils to the nerve cord surface.


In amphioxus, myomeres run longitudinally along the length of the body in a "V"-shape. As sequential contraction for swimming occurs, force from the myomeres is transmitted via connective tissues to the notochord.