340 a Tuesday , February 10 , 2015 1709-Plat Crosstalk between RyR 2 Oxidation and Phosphorylation Contributes to Cardiomyopathy in Mice with Duchenne Muscular Dystrophy

1709-Plat Crosstalk between RyR2 Oxidation and Phosphorylation Contributes to Cardiomyopathy in Mice with Duchenne Muscular Dystrophy George G. Rodney1, Qiongling Wang1, Guoliang Wang1, Xander H.T. Wehrens1,2. Molecular Physiology & Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA, Department of Medicine/ Cardiology, Baylor College of Medicine, Houton, TX, USA. Patients with Duchenne muscular dystrophy (DMD) are at risk of developing cardiomyopathy and cardiac arrhythmias. Studies in a mouse model of DMD revealed that enhanced sarcoplasmic reticulum (SR) Ca2þ leak contributes to the pathogenesis of cardiac dysfunction. In view of recent data suggesting the involvement of altered phosphorylation and oxidation of the cardiac ryanodine receptor (RyR2)/ Ca2þ release channel, we hypothesized that inhibition of RyR2 phosphorylation in a mouse model of DMD can prevent SR Ca2þ leak by reducing RyR2 oxidation. Confocal Ca2þ imaging and single RyR2 channel recordings revealed that inhibition of either S2808 or S2814 phosphorylation, or inhibition of oxidation could normalize RyR2 activity in mdx mice. Moreover, genetic inhibition of RyR2 phosphorylation at S2808 or S2814 reduced RyR2 oxidation. Production of reactive oxygen species (ROS) in myocytes from mdx mice was reduced by both inhibition of RyR2 phosphorylation or the ROS scavenger 2-mercaptoproppionylglycin (MPG). Finally, it was shown that ROS production in mdx mice is proportional to the activity of RyR2-mediated SR Ca2þ leak. We conclude that increased reactive oxygen species (ROS) production in the hearts of mdx mice drives the progression of cardiomyopathy. Inhibition of RyR2 phosphorylation can suppress SR Ca2þ leak in mdx mouse hearts in part by reducing RyR2 oxidation.