Cardiac myosin heavy chains lacking the light chain binding domain cause hypertrophic cardiomyopathy in mice

Myosin is a chemomechanical motor that converts chemical energy into the me chanical work of muscle contraction. More than 40 missense mutations in the cardiac myosin heavy chain (MHC) gene and several mutations in the two myo sin light chains cause a dominantly inherited heart disease called familial hypertrophic cardiomyopathy. Very little is known about the biochemical de fects in these alleles and how the mutations lead to disease. Because remov al of the light chain binding domain in the lever arm of MHC should alter m yosin's force transmission but not its catalytic function, we tested the hy pothesis that such a mutant MHC would act as a dominant mutation in cardiac muscle. Hearts from transgenic mice expressing this mutant myosin are asym metrically hypertrophied, with increases in mass primarily restricted to th e cardiac anterior wall. Histological examination demonstrates marked cellu lar hypertrophy, myocyte disorganization, small vessel coronary disease, an d severe valvular pathology that included thickening and plaque formation. Skinned myocytes and multicellular preparations from transgenic hearts exhi bited decreased Ca2+ sensitivity of tension and decreased relaxation rates after flash photolysis of diazo 2. These experiments demonstrate that alter ations in myosin force transmission are sufficient to trigger the developme nt of hypertrophic cardiomyopathy.