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Enhanced myosin function due to a point mutation causing a familial hypertrophic cardiomyopathy.

Most cases of familial hypertrophic cardiomyopathy have been attributed to mutations in thick or thin filament proteins in the myofibrils of myocardial cells.1 2 3 In a minority of cases, particularly those involving myosin binding protein C, such mutations have been associated with enhanced myofibrillar function, which has been inferred from changes in force and the kinetics of force development and relaxation in isolated muscle preparations and from changes in the dynamics of pressure development in working hearts. In most cases, such as those involving thin filament regulatory proteins or subunits of myosin, familial hypertrophic cardiomyopathy (FHC) mutations have been associated with depressed function in working hearts in living or skinned myocardium or in biochemical and other in vitro assays of actomyosin interaction.3 Whether myofibrillar function is enhanced or depressed, the hearts of affected individuals undergo hypertrophy as an adaptive response to altered myocardial function, and for particularly malignant mutations, there is a significantly increased probability of premature death because of mechanical or electrical abnormalities of the heart.

Although several FHC mutations have been identified using gene mapping approaches, little is known about the effects of most of the mutations on myofibrillar function or integrated contractile function in the context of human intact cardiac myocytes, muscle strips, or working hearts. However, in the case of one of these mutations, R403Q in the human β-myosin heavy chain (MHC), recent studies4 5 have taken advantage of the fact that mammalian slow muscle MHC is identical to cardiac β-MHC to obtain muscle that was heterozygous for the R403Q mutation. Biopsies from soleus muscles of individuals yielded fibers on which mechanical measurements could be made. Fibers from R403Q heterozygotes exhibited less force and slower shortening velocities than fibers from healthy homozygous individuals. The R403Q mutation has also been found to slow …