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1 Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT, USA
2 Department of Genetics, Harvard Hughes Medical Institute and Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: palmer{at}physiology.med.uvm.edu.
The kinetic effects of the cardiac myosin point mutations R403Q and R453C, which underlie lethal forms of familial hypertrophic cardiomyopathy, were assessed using isolated myosin and skinned strips taken from heterozygous (R403Q/+ and R453C/+) male mouse hearts. Compared to wild-type (WT): actin-activated ATPase was increased by 38% in R403Q/+ and reduced by 45% in R453C/+; maximal velocity of regulated thin filament (VRTF) in the in vitro motility assay was increased by 8% in R403Q/+ and was not different in R453C/+; the myosin concentration at half maximal VRTF was reduced by 30% in R403Q/+ and not different in R453C/+; and the characteristic frequency for oscillatory work production (b-frequency) determined by sinusoidal analysis in the skinned strip at maximal calcium activation was 27% lower in R403Q/+ and 18% higher in R453C/+. The calcium sensitivity for isometric tension in the skinned strip was not different in R403Q/+ (pCa50 = 5.64 ± 0.02) and significantly enhanced in R453C/+ (5.82 ± 0.03) compared to WT (5.58 ± 0.02). We conclude that isolated myosin and skinned strips of R403Q/+ and R453C/+ myocardium show marked differences in crossbridge kinetic parameters and in calcium sensitivity of force production that indicate different functional roles associated with the location of each point mutation at the molecular level.
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