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

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189 Scopus citations


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
Issue number11
StatePublished - Nov 2005


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


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