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Force development in skeletal muscle requires the interaction between the head of the myosin molecule (crossbridge)
and actin. The head of the myosin molecule contains two important regions: 1) an actin-binding site, and 2) an ATPase that derives energy from ATP for force development. Actin monomers are arranged into two filaments (thin filaments) that are twisted into a double helix and are anchored to the Z-line. Myosin molecules are arranged side by side out of phase with one another. At the same time, myosin dimers are bound tail to tail such that the myosin heads on either side of the thick filament pull toward one another. The muscle is able to generate force by the cycling of crossbridges that bind to actin. The cycling starts with an ATP molecule binding to the ATPase portion of the myosin head that is still bound to actin and is in the low-energy form. This ATP binding initiates a conformational change that removes it from actin. The ATP molecule is then split into ADP and Pi, changing the myosin head into a high-energy form (cocked). Once this energized myosin head comes in contact with an actin molecule whose binding site is exposed, the myosin will bind to the actin molecule. The release of Pi allows the myosin head to return to the low-energy form, and in the process, the myosin head pivots, pulling the Z lines of the sarcomere toward one another. The bond between actin and myosin is maintained until ATP is able to bind to the myosin head. In the absence of ATP, the muscle is maintained in the state of rigor. The cycling of crossbridges causes the two thin filaments of the sarcomere to be pulled toward one another by the thick filament, thereby pulling the Z-lines closer together.
An action potential is generated at the motor end plate by the binding of acetylcholine to the nicotinic receptor. That action potential travels along the sarcolemma and down the transverse tubules. Located within the membrane of the transverse tubules are dihydropyridine receptors that are voltage sensitive. These receptors are usually activated by depolarization. The membrane of the transverse tubule comes into contact with the sarcoplasmic reticulum, allowing the dihydropyridine receptor to directly interact with the ryanodine receptor on the sarcoplasmic reticulum. When the dihydropyridine receptor is activated by membrane depolarization from the action potential, the ryanodine receptor is stimulated to release calcium from the sarcoplasmic reticulum. As intracellular calcium increases, the release of calcium is enhanced by the binding of calcium to another calcium channel on the sarcoplasmic reticulum. In addition to their proximity to the transverse tubule, the sarcoplasmic reticulum is positioned near contractile proteins of the sarcomere to facilitate the delivery of calcium to those contractile proteins. As calcium increases within the cell, it binds to a subunit of the troponin molecule. This binding causes a conformational change in the other two troponin subunits that move the filamentous tropomyosin. At rest, tropomyosin blocks the myosin binding site on the actin molecules. Thus, the movement of tropomyosin exposes the binding site that would allow the energized myosin to interact with actin.
Energy in the form of ATP is required for the release of the actin-myosin complex, in addition to energizing the
myosin head. Thus, in order for skeletal muscle to contract, there must be an adequate supply of energy. At rest, the concentration of ATP is relatively low. In order to prevent this ATP supply from being depleted during the first few seconds of muscle contraction, creatine phosphate is present to act as an energy buffer by providing the Pi necessary to re-energize the ATP and allows crossbridge cycling to continue to break the actin-myosin complexes. Creatine phosphate is in equilibrium with creatine, whose concentration is also limited within skeletal muscle. The muscle must then switch to metabolizing glucose from its storage as glycogen in the muscle or liver (glucose must travel through the blood in order to enter the muscle). If the intensity of exercise is maintained at moderate levels or below, the aerobic metabolism of fatty acids through oxidative metabolism will take over as the primary source of energy. The fatty acids provide substrate (acetyl CoA) for the Krebs cycle and the electron transport chain as long as enough oxygen is present to act as the final accepter of electrons. However, if exercise intensity increases further, the ability of aerobic metabolism to supply energy can be compromised by the limitations on blood flow (oxygen delivery) to the active muscle. In that case, oxygen delivery would be compromised and substrate-level metabolism would have to take over the production of ATP. The byproduct of this substrate-level metabolism is lactic acid, whose dissociated hydrogen ion can limit the ability of the muscle to generate force through a number of mechanisms.
There are a number of mechanisms that contribute to alterations in force generation by individual skeletal muscle cells. The first is the frequency of stimulation. A muscle response to frequency contains two components: the treppe phenomena and the summation of contraction. Treppe describes the phenomena where an increase in frequency of stimulation (with complete relaxation between pulses) will progressively increase the force developed by the muscle until force ultimately stabilizes. The explanation for this phenomenon involves an increasing concentration of intracellular calcium, due to incomplete removal of calcium during relaxation, which elevates the force developed by the muscle cell. Summation of contraction is observed as the frequency of stimulation increases further, such that the muscle cell does not completely relax between twitches. As the frequency of twitches increases, the first twitch will not completely relax before the second twitch arrives, and so on. Thus, as frequency increases, the force generated by the muscle would continue to increase until a maximum is reached. As the frequency of stimulation increases, the muscle will eventually be able to maintain force with some oscillation around a constant value. This oscillation in force is termed tetanus. As frequency is increased further, force will eventually plateau (the trace flattens and there is no relaxation between twitches) into what is called fused (complete) tetanus or maximal tetanic tension. Prior to this force plateau (fusion), force fluctuates as the muscle cell partially relaxes between twitches, which is called unfused (incomplete) tetanus. Second, the force developed by a muscle fiber is dependent upon the diameter of that muscle fiber. As the diameter of a muscle fiber increases (number of parallel sarcomeres increases), the force generated by that muscle will increase. Finally, skeletal muscle length will affect the extent of tension development by the muscle cell. Typically, the muscle rests at near optimal length for force development. As the muscle is lengthened, the potential for interaction between actin and myosin is reduced as they slide past one another, thereby causing the force generated by the muscle to decrease. As the muscle is shortened, the extent of interaction will also be reduced by the thin filament blocking the binding of myosin and actin. In this case, force is also decreased as the muscle is shortened.
In addition to the ability of individual muscle cells to modify their force development, the force of the entire muscle can be modulated. Every muscle cell is not contracted at the same time within a muscle. Since the functional unit of the muscle is the motor unit, the extent of force development will be determined by the number of muscle fibers associated with that motor unit and the way in which those motor units are recruited. As more motor units are simultaneously recruited, the force developed by the muscle will be increased. The extent of force developed depends upon the number of muscle cells present within a given motor unit, which can vary from several hundreds to thousands. Muscles that are involved in fine movement will have fewer muscle cells per motor unit than muscles involved in more gross movement. The specific motor units activated are determined by the size principle. This principle states that there is a correspondence between the size of motor units activated and their order of recruitment. The physiological determinant of which motor units are activated is the sensitivity of the motor neurons to action potential frequency; smaller motor neurons are stimulated to generate an action potential at a lower frequency of action potentials than larger diameter motor neurons. The smaller motor units are innervated by smaller diameter motor neurons. Thus, the size of the motor units corresponds with the diameter of the motor neuron. The larger motor units are resistant to depolarization. Thus, a higher frequency of action potentials is required to activate the larger motor units. At a lower frequency, the smaller motor units will be activated. As the force required to move an object is increased, the frequency of the action potentials from the motor center is increased, thereby recruiting more of the larger fibers that are capable of generating greater force.
There are three major types of muscle fiber in human skeletal muscle, which are characterized by their metabolic profile and speed of contraction. With respect to their metabolic profile, the enzymes expressed in these cells can favor either a glycolytic (substrate-level phosphorylation) or oxidative metabolism. These alterations in enzyme profiles are supported by a number of structural differences within the muscle fibers. Muscle fibers with a greater oxidative enzyme profile will contain a greater density of capillaries, increased mitochondrial density, higher myoglobin concentration, and will have a smaller diameter than glycolytic fibers. In contrast, glycolytic fibers are thicker (have a greater diameter) than oxidative fibers, contain fewer capillaries, and have a greater capacity to produce ATP under anaerobic conditions. Thus, under high-intensity exercise, these muscles will actively produce an excess of pyruvic acid that is converted to lactic acid. The contractile properties are related to the ATPase portion of the myosin molecule. The rate of ATPase activity will greatly determine the speed with which a muscle cell can develop force. The fast fibers reach peak force sooner than the slow fibers. Putting these two properties together, the three major fiber types include slow oxidative, fast oxidative, and fast glycolytic.

Skeletal muscles generally contain differing proportions of all three skeletal muscle fiber types. However, the relative contribution of each fiber type can vary between muscles. Within a given motor unit, all of the muscle fibers are of the same fiber type, indicating that fiber type is determined by the motor neuron. The largest of the fibers are the fast glycolytic, while the smallest are the slow oxidative; the fast oxidative are intermediate. The same is true for the speed of contraction; the fast glycolytic are faster than fast oxidative, which are faster than slow oxidative. Motor units are also of different sizes; fast glycolytic are larger than fast oxidative or slow oxidative.
One reason why athletes train is to increase the capacity of their muscles to perform the work that their sport requires. Athletic training can be broken into two basic types: aerobic and anaerobic, depending upon the energy systems that are stressed by the specific training modality. In response to aerobic training, some of the fast glycolytic fibers are converted into fast oxidative fibers. This is accompanied by an increased mitochondrial density (size and number), an increase in the number of capillaries that surround each muscle fiber, and a decrease in the diameter of the muscle fiber (the last two would facilitate the delivery of oxygen to the active muscle fibers). For the slow oxidative fibers, they do not appear to be capable of converting to fast fiber types (because of the type of ATPase the myosin contains remains fairly constant). However, the changes in the slow oxidative fibers to aerobic training would be similar to the fast oxidative fibers. In contrast, high-intensity anaerobic exercise will increase the glycolytic capacity of the muscle fibers (switch some of the fast oxidative to fast glycolytic fibers). At the same time, the density of mitochondria (size and number) will be decreased, the concentration of glycolytic enzymes will be increased, and the diameter of the muscle fibers will be increased. The increased skeletal muscle girth in an individual who regularly weight trains is related to an increase in the diameter of muscle fibers (increased myofibrils) rather than an increase in the number of muscle fibers (hypertrophy rather than hyperplasia).
Contractile proteins (actin and myosin) are the same in smooth muscle and skeletal muscle. However, their arrangement within those muscle cells is quite different. Skeletal muscles are characterized by the repeating striated arrangement of the contractile proteins into sarcomeres. This is not the case for smooth muscle, where the contractile proteins are not arranged in a striated pattern, hence the smooth appearance. Rather, contractile proteins are arranged in a variety of patterns that are oblique to the long axis of the smooth muscle cell. These contractile proteins are attached to the dense bodies where the force generated by the contractile proteins is transmitted to the cell's exterior. The regulation of excitation-contraction coupling is also quite different in smooth muscle cells. Calcium is still an important regulator of force development but is coupled to contraction in a different way than was observed in skeletal muscle cells. Calcium enters the cell through a voltage-sensitive calcium channel to bind with calmodulin. The calcium-calmodulin complex binds to the enzyme myosin light-chain kinase, causing it to become active. The myosin light-chain kinase phosphorylates the myosin light chain, causing it to become active and capable of binding to actin. Thereafter, the cycling of the crossbridges is the same as observed in skeletal muscle. In order to terminate crossbridge cycling, the smooth muscle cells must do more than remove calcium from the cytoplasm. The myosin light chain must be dephosphorylated by a phosphatase enzyme. These enzymes are always active within smooth muscle cells. Thus, the extent of force developed by smooth muscle cells is dependent upon the interaction between myosin light-chain kinase and phosphatase activity, each of which can be modulated.