The myosin head transforms chemical energy from ATP hydrolysis into mechanical work to generate isometric force or to drive muscle shortening. During the power stroke, small changes in the catalytic ATPase site of the actin-bound myosin head are coupled to tilting of the light-chain binding domain relative to the catalytic domain. In this mechanism distortion of an elastic element within the actomyosin complex is essential for strain to develop prior to movement.

We have studied missense mutations naturally occurring in Familial Hypertrophic Cardiomyopathy (FHC) to test molecular mechanisms and functional roles of specific domains of the myosin head. Slow soleus muscle fibers (expressing the ventricular myosin isoform) of FHC-patients were used for these studies. Previously we found that mutation R723G which is located in the converter domain of the myosin head increases active force and resistance to elastic distortion (fiber stiffness) during contraction, relaxation, and rigor, while cross-bridge cycling kinetics were unchanged. This indicated that the converter is the part of the actomyosin complex where most of the elastic distortion occurs.

We now included mutation R453C located near the nucleotide binding pocket of myosin in our functional studies. This mutation was found to also increase active force, however, without affecting fiber stiffness. Instead, mutation R453C increased fiber ATPase activity and the rate constant of force redevelopment significantly, which were unchanged by mutation R723G. Thus, both FHC mutations cause force enhancement in muscle fibers from FHC patients, however, by distinctly different molecular mechanisms. R723G affects resistance to elastic distortion of the myosin head while R453C alters cross-bridge cycling kinetics. The data underline the different functional roles of the domains within the myosin head and points to an involvement of residue R453 in human ventricular myosin ATPase activity.