Crosstalk between RyR2 Oxidation and Phosphorylation Contributes to Cardiomyopathy in Mice with Duchenne Muscular Dystrophy

Abstract

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) Ca2+ 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)/ Ca2+ release channel, we hypothesized that inhibition of RyR2 phosphorylation in a mouse model of DMD can prevent SR Ca2+ leak by reducing RyR2 oxidation. Confocal Ca2+ 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 Ca2+ 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 Ca2+ leak in mdx mouse hearts in part by reducing RyR2 oxidation.