title: Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy.
abstract: Aberrant intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+) leak was greater in ventricular myocytes from mdx than mdx-S2808A mice. Myocytes from mdx mice had a higher incidence of isoproterenol-induced diastolic Ca(2+) release events than myocytes from mdx-S2808A mice. Thus, inhibition of PKA phosphorylation of RyR2 reduced SR Ca(2+) 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Satyam
authors.initials: S
authors.lastname: Sarma
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: van Oort
authors.forename: Corey
authors.initials: C
authors.lastname: Reynolds
authors.forename: Darlene G
authors.initials: DG
authors.lastname: Skapura
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003645:Death, Sudden / Q000517:prevention & control; D005355:Fibrosis; D006333:Heart Failure / Q000150:complications / Q000473:pathology / Q000517:prevention & control; D042541:Intracellular Space / Q000378:metabolism; D007545:Isoproterenol; D051379:Mice; D018101:Mice, Inbred mdx; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism / Q000473:pathology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D010768:Phosphoserine; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D002118:Calcium