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 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 2+ leak. Inhibiting the depletion of calstabin2 from the RyR2 complex with the Ca 2+ channel stabilizer S107 ("rycal") inhibited the SR Ca 2+ leak, inhibited aberrant depolarization in isolated cardiomyocytes, and prevented arrhythmias in vivo. This suggests that diastolic SR Ca 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 2+ leak prevents fatal sudden cardiac arrhythmias in DMD.calcium | excitation-contraction coupling | heart | sudden cardiac death | myopathy
cAMP is a powerful second messenger whose known general effector is protein kinase A (PKA). : from 2.4 ± 0.6 to 6.9 ± 1.5, P < 0.01) while reducing their amplitude (F/F 0 : 1.8 ± 0.02 versus 1.6 ± 0.01, P < 0.001) in a Ca 2+ /calmodulin kinase II (CaMKII)-dependent and PKA-independent manner. Accordingly, we found that Epac increased RyR phosphorylation at the CaMKII site. Altogether, our data reveal a new signalling pathway by which cAMP governs Ca 2+ release and signalling in cardiac myocytes.
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