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 journalArticle

32 Citations (Scopus)

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

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Inbred mdx Mouse
Ryanodine Receptor Calcium Release Channel
Cyclic AMP-Dependent Protein Kinases
Cardiomyopathies
Phosphorylation
Muscle Cells
Duchenne Muscular Dystrophy
Isoproterenol
Mortality
Alanine
Dilatation
Homeostasis
Heart Failure

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy. / Sarma, Satyam; Li, Na; Van Oort, Ralph J.; Reynolds, Corey; Skapura, Darlene G.; Wehrens, Xander H.T.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 29, 20.07.2010, p. 13165-13170.

Research output: Contribution to journalArticle

Sarma, Satyam ; Li, Na ; Van Oort, Ralph J. ; Reynolds, Corey ; Skapura, Darlene G. ; Wehrens, Xander H.T. / Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 29. pp. 13165-13170.
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