Altered crossbridge kinetics in the alpha MHC403/+ mouse model of familialhypertrophic cardiomyopathy

A mutation in the cardiac beta-myosin heavy chain, Arg403Gln (R403Q), cause s a severe form of familial hypertrophic cardiomyopathy (FHC) in humans. We used small-amplitude (0.25%) length-perturbation analysis to examine the m echanical properties of skinned left ventricular papillary muscle strips fr om mouse hearts bearing the R403Q mutation in the alpha-myosin heavy chain (alpha MHC403/+). Myofibrillar disarray with variable penetrance occurred i n the left ventricular free wall of the alpha MHC403/+ hearts. In resting s trips (pCa 8), dynamic stiffness was approximate to 40% greater than in wil d-type strips, consistent with elevated diastolic stiffness reported for mu rine hearts with FHC. At pCa 6 (submaximal activation), strip isometric ten sion was approximate to 3 times higher than for wild-type strips, whereas a t pCa 5 (maximal activation), tension was marginally lower. At submaximal c alcium activation the characteristic frequencies of the work-producing (6) and work-absorbing (c) steps of the crossbridge were less in alpha MHC403/ strips than in wild-type strips (b=11+/-1 versus 15+/-1 Hz; c=58+/-3 versu s 66+/-3 Hz: 27 degrees C). At maximal calcium activation, strip oscillator y power was reduced (0.53+/-0.25 versus 1.03+/-0.18 mW/mm(3); 27 degrees C) , which is partly attributable to the reduced frequency b, at which crossbr idge work is maximum. The results are consistent with the hypothesis that t he R403Q mutation reduces the strong binding affinity of myosin for actin, Myosin heads may accumulate in a preforce state that promotes cooperative a ctivation of the thin filament at submaximal calcium but blunts maximal ten sion and oscillatory power output at maximal calcium. The calcium-dependent effect of the mutation (whether facilitating or debilitating), together wi th a variable degree of fibrosis and myofibrillar disorder, may contribute to the diversity of clinical symptoms observed in murine FHC.