Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Satyam Sarma, Na Li, Ralph J. Van Oort, Corey Reynolds, Darlene G. Skapura, Xander H.T. Wehrens

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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 Ca 2+ homeostasis associated with dystrophic cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)13165-13170
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number29
DOIs
StatePublished - Jul 20 2010

Keywords

  • Calcium
  • Cardiomyopathy
  • Dystrophin
  • Ryanodine receptor
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy'. Together they form a unique fingerprint.

Cite this