期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 29, 页码 13165-13170出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1004509107
关键词
calcium; cardiomyopathy; dystrophin; ryanodine receptor; sarcoplasmic reticulum
资金
- W.M. Keck Foundation
- Muscular Dystrophy Association [69238]
- National Institutes of Health (NIH)/National Heart Lung, and Blood Institute [R01-HL089598, R01-HL091947]
- NIH [T32-HL007706-15]
- Heart Rhythm Society
- Fondation Leducq
Aberrant intracellular Ca2+ regulation is believed to contribute to the development of cardiomyopathy in Duchenne muscular dystrophy. Here, we tested whether inhibition of protein kinase A (PKA) phosphorylation of ryanodine receptor type 2 (RyR2) prevents dystrophic cardiomyopathy by reducing SR Ca2+ leak in the mdx mouse model of Duchenne muscular dystrophy. mdx mice were crossed with RyR2-S2808A mice, in which PKA phosphorylation site S2808 on RyR2 is inactivated by alanine substitution. Compared with mdx mice that developed age-dependent heart failure, mdx-S2808A mice exhibited improved fractional shortening and reduced cardiac dilation. Whereas application of isoproterenol severely depressed cardiac contractility and caused 95% mortality in mdx mice, contractility was preserved with only 19% mortality in mdx-S2808A mice. SR Ca2+ leak was greater in ventricular myocytes from mdx than mdx-S2808A mice. Myocytes from mdx mice had a higher incidence of isoproterenol-induced diastolic Ca2+ release events than myocytes from mdx-S2808A mice. Thus, inhibition of PKA phosphorylation of RyR2 reduced SR Ca2+ leak and attenuated cardiomyopathy in mdx mice, suggesting that enhanced PKA phosphorylation of RyR2 at S2808 contributes to abnormal Ca2+ homeostasis associated with dystrophic cardiomyopathy.
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