Elastic distortion of the actomyosin complex is fundamental to force generation in striated muscle. During isometric contraction, actin and myosin filaments cannot directly follow the rotation of the light-chain (LC) binding domain during the myosin power stroke. Instead, the myosin head as well as actin and myosin filaments become elastically distorted, thus generating muscle force. Despite this fundamental relevance, it remained unclear which structural element of the myosin head domain becomes elastically distorted. It was believed that it is the LC binding domain, i.e., the lever arm that becomes elastically distorted.

We addressed this question by studying functional effects of three naturally occurring familial hypertrophic cardiomyopathy (FHC)-related missense mutations in the myosin head domain (Arg723Gly, Arg719Trp and Ile736Thr) in human soleus muscle fibers. The mutations are located in the converter domain of the myosin head, which forms the link between LC domain and catalytic domain.

Two mutations located near the long a-helix of the LC domain increased active force and resistance to elastic distortion (fiber stiffness) in contraction, relaxation, and rigor, while cross-bridge cycling kinetics were unchanged. A mutation near the converter surface did not affect any of these parameters.

Increased resistance to elastic distortion by mutations in the converter domain implies that the converter is the part of the myosin head where most elastic distortion occurs while other parts act more like rigid bodies. Our data show the potential of FHC-mutations to provide new insight in the molecular functioning of the myosin head domain, i.e., to identify functional relevance of the different subdomains of the myosin head.