Abstract
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.
Users
Please
log in to take part in the discussion (add own reviews or comments).