The process by which the contraction of muscle is brought about is a sliding of the thin filaments over the thick filaments. Note that this shortening is not due to changes in the actual lengths of the thick and thin filaments, rather, by their increased overlap within the muscle cell. The width of the A bands is constant, whereas the Z lines move closer together when the muscle contracts and farther apart when it relaxes (Figure 1).
Fig1. Skeletal muscle sarcomere. A) Electron micrograph of human gastrocnemius muscle (× 13,500). The sarcomere, named bands, and lines are shown. (Used with permission from GM Walker and GR Schrodt.) B) Arrangement of thin (actin) and thick (myosin) filaments and the Z line in a relaxed skeletal muscle. C) Arrangement of thin and thick filaments and the Z-line in a contracted skeletal muscle. Note that the Z-lines come together as the thick and thin filaments slide next to each other during contraction. The thick and think filaments do not change in size.
The sliding during muscle contraction occurs when the myosin heads bind firmly to actin, bend at the junction of the head with the neck, and then detach. This “power stroke” depends on the simultaneous hydrolysis of ATP. Myosin-II molecules are dimers that have two heads, but only one attaches to actin at any given time. The probable sequence of events of the power stroke is outlined in Figure 2. In resting muscle, troponin I is bound to actin and tropomyosin and covers the sites where myosin heads interact with actin. Also at rest, the myosin head contains tightly bound adenosine phosphate (ADP). Following an action potential, cytosolic Ca2+ is increased and free Ca2+ binds to troponin C. This binding results in a weakening of the troponin I interaction with actin and exposes the actin binding site for myosin to allow for formation of myosin/actin cross-bridges. Upon formation of the cross-bridge, ADP is released, causing a conformational change in the myosin head that moves the thin filament relative to the thick filament, comprising the cross-bridge “power stroke.” ATP quickly binds to the free site on the myosin, which leads to a detachment of the myosin head from the thin filament. ATP is hydrolyzed and inorganic phosphate (Pi ) released, causing a “re-cocking” of the myosin head and completing the cycle. As long as Ca2+ remains elevated and sufficient ATP is available, this cycle repeats. Many myosin heads cycle at or near the same time, and they cycle repeatedly, producing gross muscle contraction. Each power stroke shortens the sarcomere about 10 nm. Each thick filament has about 500 myosin heads, and each head cycles about five times per second during a rapid contraction.
Fig2. Power stroke of myosin in skeletal muscle. A) At rest, myosin heads are bound to adenosine diphosphate and are said to be in a “cocked” position in relation to the thin filament, which does not have Ca2+ bound to the troponin—tropomyosin complex. B) Ca2+ bound to the troponin—tropomyosin complex induces a conformational change in the thin filament that allows for myosin heads to cross-bridge with thin filament actin. C) Myosin heads rotate, move the attached actin and shorten the muscle fiber, forming the power stroke. D) At the end of the power stroke, ATP binds to a now exposed site, and causes a detachment from the actin filament. E) ATP is hydrolyzed into ADP and inorganic phosphate (Pi ) and this chemical energy is used to “re-cock” the myosin head. (Data from Huxley AF, Simmons RM: Proposed mechanism of force generation in striated muscle. Nature Oct 22;233(5321):533–538, 1971 and Squire JM: Molecular mechanisms in muscular contraction. Trends Neurosci 6:409–413, 1093.)
The process by which depolarization of the muscle fiber initiates contraction is called excitation–contraction coupling. The action potential is transmitted to all the fibrils in the fiber via the T system (Figure 3). It triggers the release of Ca2+ from the terminal cisterns, the lateral sacs of the sarcoplasmic reticulum next to the T system. Depolarization of the T tubule membrane activates the sarcoplasmic reticulum via dihydropyridine receptors (DHPR), named for the drug dihydropyridine, which blocks them (Figure 4). DHPR are voltage-gated Ca2+ channels in the T tubule membrane. In cardiac muscle, influx of Ca2+ via these channels triggers the release of Ca2+ stored in the sarcoplasmic reticulum (calcium induced calcium release) by activating the ryanodine receptor (RyR). The RyR is named after the plant alkaloid ryanodine that was used in its discovery. The RyR is a ligand-gated Ca2+ channel with Ca2+ as its natural ligand. In skeletal muscle, Ca2+ entry from the extracellular fluid (ECF) by this route is not required for Ca2+ release. Instead, the DHPR that serves as the voltage sensor unlocks release of Ca2+ from the nearby sarcoplasmic reticulum via physical interaction with the RyR. The released Ca2+ is quickly amplified through calcium induced calcium release. Ca2+ concentration is reduced in the muscle cell by the sarcoplasmic or endoplasmic reticulum Ca2+ ATPase (SERCA). The SERCA pump uses energy from ATP hydrolysis to remove Ca2+ from the cytosol back into the terminal cisterns, where it is stored until released by the next action potential. Once the Ca2+ concentration outside the sarcoplasmic reticulum has been lowered sufficiently, chemical interaction between myosin and actin ceases and the muscle relaxes. Note that ATP provides the energy for both contraction (at the myosin head) and relaxation (via SERCA). If transport of Ca2+ into the sarcoplasmic reticulum is inhibited, relaxation does not occur even though there are no more action potentials; the resulting sustained contraction is called a contracture. Alterations in the excitable response in muscle underscore many different pathologies (Clinical Box 1).
Fig3. Flow of information that leads to muscle contraction.
Fig4. Relation of the T tubule to the sarcoplasmic reticulum in Ca2+ transport. In skeletal muscle, the voltage-gated dihydropyridine receptor in the T tubule triggers Ca2+ release from the sarcoplasmic reticulum (SR) via the ryanodine receptor (RyR). Upon sensing a voltage change, there is a physical interaction between the sarcolemmal-bound DHPR and the SR-bound RyR. This interaction gates the RyR and allows for Ca2+ release from the SR.
