Key result
Murine models with S532P and F764L cardiac myosin missense mutations developed dilated cardiomyopathy phenotypes with depressed myocyte contractile function and reduced actin translocation.
Why the study?
Do missense mutations (S532P and F764L) in alpha-cardiac myosin heavy chain cause dilated cardiomyopathy and depress molecular motor function in murine models?
Do missense mutations (S532P and F764L) in alpha-cardiac myosin heavy chain cause dilated cardiomyopathy and depress molecular motor function in murine models?
Missense mutations in cardiac myosin depress molecular motor function, which may initiate the events leading to pathological remodeling and dilated cardiomyopathy.
Myosin motor defects may initiate DCM remodeling in models; leaves open human translation and therapeutic targeting.
Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.
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Schmitt et al. (2006) studied Dilated cardiomyopathy. S532P and F764L missense mutations in alpha-cardiac myosin heavy chain vs. WT mice was evaluated on Morphological and functional characteristics of DCM, contractile function, actin translocation, and ATPase activities. Murine models with S532P and F764L cardiac myosin missense mutations developed dilated cardiomyopathy phenotypes with depressed myocyte contractile function and reduced actin translocation.
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