The basic building block of the contractile system is the sarcomere12 (Fig. 3-7), a recurring arrangement of the proteins responsible for mechanical activity. Adult myocytes are capable of increasing the numbers and changing the arrangement of sarcomeres in response to physiologic or pathologic changes in demands. An increase in sarcomeres in parallel increases force-producing capacity; an increase in series increases shortening capacity. Each sarcomere is composed of two bundles of longitudinally oriented filaments.12 Thick filaments, approximately 1.6 Mm long, are composed of myosin molecules in a trigonal array at the center of the sarcomere's length. Cardiac myosin is a member of a large family of myosins that function in various molecular motors. In addition to myosin, two other proteins are associated with the thick filament, titin and myosin-binding protein C. At each end of this array, a set of approximately 1-Mm-long thin filaments composed of actin and the proteins tropomyosin (Tm) and troponin (Tn) interdigitates with the thick filaments. The other ends of the thin filaments extend to the ends of the sarcomere, where they attach to a transverse structure, the Z-line. The distance between sequential Z-lines is the sarcomere length. At a length of 2.2 Mm (length at which maximal force is produced), the central end of each thin filament overlaps 0.7 Mm of the distal ends of the thick filaments (the overlap zone). The 0.3-Mm length of nonoverlapped thin filaments extending to the Z-line and the corresponding 0.3 Mm of nonoverlapped thin filaments in the adjacent sarcomere constitute the I-band. The centrally positioned thick filaments constitute the A-band. Alternating A- and I-bands are responsible for the striated appearance of cardiac muscle. Thick filaments are joined at the M-line in the middle of the sarcomere.
As just indicated, a portion of each myosin molecule is oriented longitudinally to form the thick filament. In addition, a portion of the molecule protrudes from the thick filament surface and can move freely in the space between the thick and thin filaments Fig. 3-8, Plate 28). This protruding portion includes the myosin heavy chain that forms the crossbridge, the molecular structure that interacts with actin and is responsible for conversion of chemical energy (high-energy phosphate bonds) to mechanical energy (force and motion).35,36 The crossbridge head (myosin heavy chain) is a complex protein containing a domain that binds with actin and a site of ATPase activity.37,38 Two auxiliary proteins (light chains) that have a role in maintaining the structural requirements for force generation (essential light chain) and providing fine control of force and motion (regulatory light chain) are adsorbed to the surface of the heavy chain. In mammalian cardiac muscle, myosin heavy chain exists primarily as two isoforms, alpha and beta.37 The alpha isoform has higher ATPase activity and more rapid rates of crossbridge formation and velocity than beta and is dominant in adult small mammals.38-42 The beta isoform is dominant in adult large mammals, including humans. Titin is a giant protein anchored in the Z-line on one end and closely associated with myosin on its other end.43 A segment of titin has springlike properties and is an important determinant of the passive viscoelasticity of the myocyte43,44 and, in turn, the ventricle. When cardiac muscle contracts below its slack, or unstressed, length, titin is compressed and recoils to its rest length.43,44 This restoring force may have a role in diastolic suction (see below). Myosin-binding protein C is bound to both myosin and titin. It appears to have a role in sarcomere assembly and also may modulate myosin ATPase activity by virtue of variations in its phosphorylation.45
Actin monomers are arranged in a double helix to form the core of the thin filament46 48 Figs. 3-8,
'3-9 >Plate 28, and ). Tm is adsorbed longitudinally along the thin filament. Each molecule spans seven actin monomers, with a short overlap segment at the ends of adjacent Tms. Tn, composed of three subunit proteins, TnC, TnI, and TnT, is adsorbed on Tm, also in a ratio of 1 per 7 actin monomers. TnC contains a Ca-binding site, TnI variably binds to Tm and TnC (depending on activation), and TnT links Tn to Tm at the overlap zone. The combined Tm-Tn complex is responsible for the ability of Ca ions, binding to TnC, to act as a switch initiating crossbridge formation. TnI and TnT, the myosin regulatory light chain, and myosin-binding protein C all have phosphorylatable sites (mainly serines and threonines).48,49 Phosphorylation of these contractile proteins, especially TnI and TnT, modulates the activity of myosin
ATPase, as described below.
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