Defective RYR2 Channels Trigger Ventricular Arrhythmias in Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) affects one in 3500 newborn males and usually leads to death from respiratory or cardiac failure by age 30. Interestingly, the severity of cardiomyopathy is not proportional to the severity of skeletal muscle disorder. Among DMD patients, the cardiac phenotype varies with age from no discernable cardiac left ventricular enlargement or dysfunction to early onset of dilated cardiomyopathy (DCM) with heart failure. The incidence of DCM in DMD patients has been estimated to be 25% by 6 years of age, 59% at 10 years of age and ∼100% in adults. DMD patients often exhibit electrocardiographic abnormalities and frequent premature ventricular contractions. As the cardiomyopathy progresses, ventricular arrhythmias (VA) increase, often leading to sudden death. Most of the electrical and functional abnormalities have been attributed to cardiac fibrosis. However, electrical abnormalities may occur in the absence of overt cardiac histopathology and ECG changes are similar in patients with DMD regardless of presence of DCM.Here we show that structural and functional remodeling of the cardiac sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR2) occurs in the mdx mouse model of DMD. RyR2 from mdx hearts were S-nitrosylated and depleted of calstabin2 (FKBP12.6) resulting in “leaky” RyR2 channels and diastolic SR Ca2+ leak. Inhibiting the depletion of calstabin2 from the RyR2 complex with the calcium channel stabilizer, S107 (“rycal”), inhibited the SR Ca2+ leak, restored normal Ca2+ transients, inhibited isoproterenol induced aberrant depolarizations in isolated cardiomyocytes and prevented arrhythmias in vivo.Thus, diastolic SR Ca2+ leak via RyR2 due to S-nitrosylation of the channel and calstabin2 depletion from the channel complex likely triggers cardiac arrhythmias. Prevention of the RyR2-mediated diastolic SR Ca2+ leak may provide a novel cardiac therapeutic approach in DMD.