Abstract
The kinetic effects of the cardiac myosin point mutations R403Q and
R453C, which underlie lethal forms of familial hypertrophic cardiomyopathy
(FHC), were assessed using isolated myosin and skinned strips taken
from heterozygous (R403Q/+ and R453C/+) male mouse hearts. Compared
with wild-type (WT) mice, actin-activated ATPase was increased by
38% in R403Q/+ and reduced by 45% in R453C/+, maximal velocity of
regulated thin filament (V(RTF)) in the in vitro motility assay was
increased by 8% in R403Q/+ and was not different in R453C/+, myosin
concentration at half-maximal V(RTF) 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/+
(pCa(50) 5.64 +/- 0.02) and significantly enhanced in R453C/+ (5.82
+/- 0.03) compared with WT (5.58 +/- 0.02). We conclude that isolated
myosin and skinned strips of R403Q/+ and R453C/+ myocardium show
marked differences in cross-bridge 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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