Cardiac myosin-binding protein-C phosphorylation and cardiac function

Sakthivel Sadayappan, James Gulick, Hanna Osinska, Lisa A. Martin, Harvey S. Hahn, Gerald W. Dorn, Raisa Klevitsky, Christine E. Seidman, Jonathan G. Seidman, Jeffrey Robbins

Research output: Contribution to journalArticlepeer-review

173 Scopus citations

Abstract

The role of cardiac myosin binding protein-C (cMyBP-C) phosphorylation in cardiac physiology or pathophysiology is unclear. To investigate the status of cMyBP-C phosphorylation in vivo, we determined its phosphorylation state in stressed and unstressed mouse hearts. cMyBP-C phosphorylation is significantly decreased during the development of heart failure or pathologic hypertrophy. We then generated transgenic (TG) mice in which the phosphorylation sites of cMyBP-C were changed to nonphosphorylatable alanines (MyBP-CAllP-). A TG line showing ≈40% replacement with MyBP-CAllP- showed no changes in morbidity or mortality but displayed depressed cardiac contractility, altered sarcomeric structure and upregulation of transcripts associated with a hypertrophic response. To explore the effect of complete replacement of endogenous cMyBP-C with MyBP-CAllP-, the mice were bred into the MyBP-C(t/t) background, in which less than 10% of normal levels of a truncated MyBP-C are present. Although MyBP-CAllP- was incorporated into the sarcomere and expressed at normal levels, the mutant protein could not rescue the MyBP-C(t/t) phenotype. The mice developed significant cardiac hypertrophy with myofibrillar disarray and fibrosis, similar to what was observed in the MyBP-C(t/t) animals. In contrast, when the MyBP-C(t/t) mice were bred to a TG line expressing normal MyBP-C (MyBP-CWT), the MyBP-C(t/t) phenotype was rescued. These data suggest that cMyBP-C phosphorylation is essential for normal cardiac function.

Original languageEnglish
Pages (from-to)1156-1163
Number of pages8
JournalCirculation research
Volume97
Issue number11
DOIs
StatePublished - Nov 2005

Keywords

  • Mouse
  • Mouse mutants
  • Muscle
  • Muscle contraction
  • Myocardial contractility

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