Myosin is a major protein involved in muscle contraction and force production. Eight isoforms of the myosin heavy chain (MyHC) component of myosin have been identified in striated muscle: six adult isoforms and two developmental isoforms. Muscle diseases have been linked to mutations in the MyHC genes. The most common of these is familial hypertrophic cardiomyopathy (HCM), which is associated with mutations in the Beta cardiac MyHC. In addition, recent work has identified a missense mutation in the MyHC-IIa gene that results in a dominantly inherited skeletal myopathy. While some of the cardiac MyHC mutations and their effects have been extensively characterized in both human patients and animal models, to date there is little information on the effects of such missense mutations in skeletal muscle. To better understand the pathogenesis of myosin-based skeletal myopathies, and to relate the disease process in skeletal muscle to that of the heart, transgenic mouse strains expressing mutations in the MyHC-IIb gene will be generated. Given both the similarities and differences in cardiac and skeletal muscle function, it will be insightful to compare the impact of a mutation known to cause well-characterized heart disease in skeletal muscle. To meet this aim, a mutation that results in severe HCM (R403Q) will be expressed in skeletal muscle in order to characterize its effects. In addition, a mouse model expressing the mutation associated with the dominantly inherited skeletal myopathy (E706K) will be created in order to further investigate the molecular mechanisms and physiology underlying the condition.
