Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy.
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.
Sarma
Satyam
S
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Li
Na
N
van Oort
Ralph J
RJ
Reynolds
Corey
C
Skapura
Darlene G
DG
Wehrens
Xander H T
XH
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
D019837:Ryanodine Receptor Calcium Release Channel; D010768:Phosphoserine; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D002118:Calcium