Published online before print October 13, 2005, doi: 10.1161/01.RES.0000190605.79013.4d
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© 2005 American Heart Association, Inc.
Cellular Biology |
Cardiac Myosin-Binding Protein-C Phosphorylation and Cardiac Function
From the Department of Pediatrics (S.S., J.G., H.O., R.K., L.A.M., J.R), Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, OH; Department of Medicine (H.S.H., G.W.D), University of Cincinnati, OH; Department of Genetics (C.E.S., J.G.S), Howard Hughes Medical Institute and Harvard Medical School, Boston, Mass; and Cardiovascular Division (C.E.S.), Brigham and Women’s Hospital, Boston, Mass.
Correspondence to Jeffrey Robbins, MLC 7020, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.robbins{at}cchmc.org
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.
Key Words: mouse • mouse mutants • muscle • muscle contraction • myocardial contractility
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