The highly specialized contractile machinery in muscle cells is thought to have evolved from the simpler contractile bundles of myosin and actin filaments found in all eukaryotic cells. The myosin-II in nonmuscle cells is also activated by a rise in cytosolic Ca 2+ , but the mechanism of activation is different from that of the muscle-specific myosin-II. An increase in Ca 2+ leads to the phosphorylation of nonmuscle myosin-II, which alters the myosin conformation and enables it to interact with actin.

A similar activation mechanism operates in smooth muscle, which is present in the walls of the stomach, intestine, uterus, and arteries, and in many other structures that undergo slow and sustained involuntary contractions. This mode of myosin activation is relatively slow, because time is needed for enzyme molecules to diffuse to the myosin heads and carry out the phosphorylation and subsequent dephosphorylation.

However, this mechanism has the advantage that—unlike the mechanism used by skeletal muscle cells—it can be activated by a variety of extracellular signals: thus smooth muscle, for example, is triggered to contract by epinephrine, serotonin, prostaglandins, and several other signal molecules.

In addition to skeletal and smooth muscle, other forms of muscle each perform a specific mechanical function. Heart—or cardiac—muscle, for instance, drives the circulation of blood. The heart contracts autonomously for the entire life of the organism—some 3 billion (3 × 10 9 ) times in an average human lifetime. Even subtle abnormalities in the actin or myosin of heart muscle can lead to serious disease. For example, mutations in the genes that encode cardiac myosin-II or other proteins in the sarcomere cause familial hypertrophic cardiomyopathy, a hereditary disorder responsible for sudden death in young athletes.