The normal cardiac contractile apparatus is such a highly tuned machine that a tiny abnormality anywhere in the works can be enough to gradually wear it down over years of repetitive motion. Familial hypertrophic cardiomyopathy is a common cause of sudden death in young athletes. It is a genetically dominant inherited condition that affects about two out of every thousand people, and it is associated with heart enlargement, abnormally small coronary vessels, and disturbances in heart rhythm (cardiac arrhythmias). The cause of this condition is either any one of over 40 subtle point mutations in the genes encoding cardiac β myosin heavy chain (almost all causing changes in or near the motor domain) or one of about a dozen mutations in other genes encoding contractile proteins— including myosin light chains, cardiac troponin, and tropomyosin. Minor mis-sense mutations in the cardiac actin gene cause another type of heart condition, called dilated cardiomyopathy, which can also result in early heart failure.
Actin and Myosin Perform a Variety of Functions in Non-Muscle Cells
Most non-muscle cells contain small amounts of contractile actin–myosin II bundles that form transiently under specific conditions and are much less well organized than muscle fibers. Non-muscle contractile bundles are regulated by myosin phosphorylation rather than the troponin mechanism (Figure 16–39). These contractile bundles function to provide mechanical support to cells, for example, by assembling into cortical stress fibers that connect the cell to the extracellular bipolar flament of 15–20 molecules
Figure 16–38 Effect on the heart of a subtle mutation in cardiac myosin. Left, normal heart from a 6-day-old mouse pup. Right, heart from a pup with a point mutation in both copies of its cardiac myosin gene, changing Arg403 to Gln. The arrows indicate the atria. In the heart from the pup with the cardiac myosin mutation, both atria are greatly enlarged (hypertrophic), and the mice die within a few weeks of birth. (From D. Fatkin et al.,
J. Clin. Invest. 103:147–153, 1999. With permission from The American Society for Clinical Investigation.)
Figure 16–39 Light-chain phosphorylation and the regulation of the assembly of myosin II into thick filaments. (A) The controlled phosphorylation by the enzyme myosin light-chain kinase (MLCK) of one of the two light chains (the so-called regulatory light chain, shown in light blue) on non-muscle myosin II in a test tube has at least two effects: it causes a change in the conformation of the myosin head, exposing its actinbinding site, and it releases the myosin tail from a “sticky patch” on the myosin head, thereby allowing the myosin molecules to assemble into short, bipolar, thick filaments. Smooth muscle is regulated by the same mechanism (see Figure 16–37). (B) Electron micrograph of negatively stained short filaments of myosin II that have been induced to assemble in a test tube by phosphorylation of their light chains. These myosin II filaments are much smaller than those found in skeletal muscle cells (see Figure 16–27). (B, courtesy of John Kendrick-Jones.) matrix through focal adhesions or by forming a circumferential belt in an epithelial cell, connecting it to adjacent cells through adherens junctions (discussed in Chapter 19). As described in Chapter 17, actin and myosin II in the contractile ring generate the force for cytokinesis, the final stage in cell division. Finally, as discussed later, contractile bundles also contribute to the adhesion and forward motion of migrating cells.