Transgenic mice expressing a mutant MyBP-C lacking the myosin binding site showed very modest levels of mutant protein but significant changes in cardiac structure and decreased fiber mechanics.
In a transgenic mouse model, a MyBP-C mutation lacking the myosin binding site causes significant structural and mechanical cardiac deficits despite low mutant protein expression.
Myosin binding protein C (MyBP-C) is an integral part of the striated muscle sarcomere. As is the case for other sarcomeric genes in human populations, multiple mutations within the gene have been linked to familial hypertrophic cardiomyopathy. Although some MyBP-C lesions are the result of missense mutations, most show truncated polypeptides lacking either the myosin or myosin and titin binding sites. Previously, we generated transgenic (TG) mice with cardiac-specific expression of a MyBP-C mutant lacking the myosin and titin binding domains. Surprisingly, the mutant protein was stable and made up a majority of the MyBP-C species, with concomitant reductions in endogenous MyBP-C such that overall MyBP-C stoichiometry was conserved. In the present study, we created a second series of TG mice that express, in the heart, a mutant MyBP-C lacking only the myosin binding site. In contrast to the previous data for the MyBP-C lacking both titin and myosin binding sites, only very modest levels of protein were found, consistent with data obtained from human biopsies in which mutated MyBP-C could not be detected. Despite normal levels of wild-type MyBP-C, there were significant changes in the structure and ultrastructure of the heart. Fiber mechanics showed decreased unloading shortening velocity, maximum shortening velocity, and relative maximal power output.
Yang et al. (Fri,) conducted a other in Familial hypertrophic cardiomyopathy. Transgenic expression of a mutant MyBP-C lacking the myosin binding site vs. Wild-type / previous TG mice lacking both titin and myosin binding sites was evaluated on Changes in structure, ultrastructure, and fiber mechanics. Transgenic mice expressing a mutant MyBP-C lacking the myosin binding site showed very modest levels of mutant protein but significant changes in cardiac structure and decreased fiber mechanics.