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Heterologous expression of wild-type and mutant -cardiac myosin changes the contractile kinetics of cultured mouse myotubes

Gaynor Miller, Joanne Maycock, Ed White, Michelle Peckham and Sarah Calaghan

The properties of myosin expressed in muscle are a major determinant of muscle performance. In this study we used a novel approach to examine the functional impact of changes in myosin heavy chain (MHC) isoform expression, as well as the consequences of expressing the mutant MHC implicated in familial hypertrophic cardiomyopathy (FHC). Cultured mouse myoblasts that normally express fast embryonic myosin were untransfected, or stably transfected with a plasmid expressing either wild-type (cWT) or mutant (D778G or G741R) -cardiac myosin. After differentiation for 5-7 days, cWT or mutant -cardiac myosin was expressed at 25 % of total myosin in the myotube. We measured time-to-peak shortening (ttp), time for half-relaxation (t_0.5), the maximum velocity of shortening (V_max) at 1 Hz stimulation, and the tetanic fusion frequency. Expression of cWT -cardiac myosin significantly increased ttp and t_0.5 and decreased the fusion frequency compared with untransfected myotubes. However, when we compared myotubes expressing mutant -cardiac myosin with those expressing cWT -cardiac myosin, we found that ttp and t_0.5 were significantly decreased, and V_max was increased for the D778G mutant, whereas ttp, t_0.5 and V_max were unchanged for the G741R mutant. The fusion frequency was increased for both mutant myosins. Our data support the conclusion that the impact of the slower myosin isoform dominates when both slow and fast isoforms are present. This work suggests that FHC associated with either D778G or G741R mutation in MHC is an 'energy cost' disease, but that the phenotype of D778G is more severe than that of G741R.

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