In vivo modeling of myosin binding protein C familial hypertrophic cardiomyopathy

Qinglin Yang, Atsushi Sanbe, Hanna Osinska, Timothy E. Hewett, Raisa Klevitsky, Jeffrey Robbins

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)841-847
Number of pages7
JournalCirculation research
Volume85
Issue number9
DOIs
StatePublished - Oct 29 1999

Keywords

  • Cardiac disease
  • Muscle
  • Myosin
  • Transgenic

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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