© 1999 American Heart Association, Inc.
Original Contribution |
Altered Crossbridge Kinetics in the 
MHC403/+ Mouse Model of Familial Hypertrophic Cardiomyopathy
From the Department of Molecular Physiology and Biophysics (E.B., D.M.), University of Vermont Medical School, Burlington, Vt; Department of Medicine (C.S.), Brigham and Women's Hospital, and Howard Hughes Institute and Department of Genetics (J.G.S.), Harvard Medical School, Boston, Mass; and Cardiology Unit (M.L.), University of Vermont Medical School, Burlington, Vt.
Abstract—A mutation in the
cardiac ß-myosin heavy chain, Arg403Gln (R403Q), causes a severe form
of familial hypertrophic cardiomyopathy (FHC) in
humans. We used small-amplitude (0.25%) length-perturbation
analysis to examine the mechanical properties of skinned left
ventricular papillary muscle strips from mouse hearts
bearing the R403Q mutation in the 
-myosin heavy chain
(MHC403/+). Myofibrillar disarray with
variable penetrance occurred in the left ventricular
free wall of the MHC403/+ hearts. In resting strips (pCa
8), dynamic stiffness was 
40% greater than in wild-type strips,
consistent with elevated diastolic stiffness
reported for murine hearts with FHC. At pCa 6 (submaximal activation),
strip isometric tension was 3 times higher than for wild-type
strips, whereas at pCa 5 (maximal activation), tension was marginally
lower. At submaximal calcium activation the characteristic frequencies
of the work-producing (b) and work-absorbing
(c) steps of the crossbridge were less in
MHC403/+ strips than in wild-type strips
(b=11±1 versus 15±1 Hz; c= 58±3 versus
66±3 Hz; 27°C). At maximal calcium activation, strip oscillatory
power was reduced (0.53±0.25 versus 1.03±0.18 mW/mm3;
27°C), which is partly attributable to the reduced frequency
b, at which crossbridge work is maximum. The results are
consistent with the hypothesis that the R403Q mutation reduces
the strong binding affinity of myosin for actin. Myosin heads may
accumulate in a preforce state that promotes cooperative activation of
the thin filament at submaximal calcium but blunts maximal tension and
oscillatory power output at maximal calcium. The calcium-dependent
effect of the mutation (whether facilitating or debilitating), together
with a variable degree of fibrosis and myofibrillar disorder, may
contribute to the diversity of clinical symptoms observed in
murine FHC.
Key Words: cardiomyopathy • myosin mutation • mouse • crossbridge kinetics
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