Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy

Patients with Duchenne muscular dystrophy (DMD) have a progressive dilated cardiomyopathy associated with fatal cardiac arrhythmias. Electrical and functional abnormalities have been attributed to cardiac fibrosis; however, electrical abnormalities may occur in the absence of overt cardiac histopathology. Here we show that structural and functional remodeling of the cardiac sarcoplasmic reticulum (SR) [Ca.sup.2+] 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 a diastolic SR [Ca.sup.2+] leak. Inhibiting the depletion of calstabin2 from the RyR2 complex with the [Ca.sup.2+] channel stabilizer S107 ('rycal') inhibited the SR [Ca.sup.2+] leak, inhibited aberrant depolarization in isolated cardiomyocytes, and prevented arrhythmias in vivo. This suggests that diastolic SR [Ca.sup.2+] leak via RyR2 due to S-nitrosylation of the channel and calstabin2 depletion from the channel complex likely triggers cardiac arrhythmias. Normalization of the RyR2-mediated diastolic SR [Ca.sup.2+] leak prevents fatal sudden cardiac arrhythmias in DMD. calcium | excitation-contraction coupling | heart | sudden cardiac death | myopathy doi/ 10.1073/pnas.0908540107