Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy

• DOI: 10.1073/pnas.0908540107
• Publication Date: 2010-01-05T02:36:36Z
• Authors: Jérémy Fauconnier; Jérôme Thireau; Steven Reiken; Cécile Cassan; Sylvain Richard; Stefan Matecki; Andrew R. Marks; Alain Lacampagne
• Keywords: Male; 0301 basic medicine; calcium; Heart Ventricles; excitation-contraction coupling; Arrhythmias, Cardiac; Ryanodine Receptor Calcium Release Channel; heart; sudden cardiac death; 3. Good health; Mice, Inbred C57BL; Muscular Dystrophy, Duchenne; Tacrolimus Binding Proteins; Disease Models, Animal; Mice; Sarcoplasmic Reticulum; 03 medical and health sciences; [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]; Mice, Inbred mdx; Animals; Calcium; myopathy

Patients with Duchenne muscular dystrophy (DMD) have a progressive dilated cardiomyopathy associated fatal cardiac arrhythmias. Electrical and functional abnormalities been attributed to fibrosis; however, electrical may occur in the absence of overt histopathology. Here we show that structural remodeling sarcoplasmic reticulum (SR) Ca 2+ release channel/ryanodine receptor (RyR2) occurs mdx mouse model DMD. RyR2 from hearts were S-nitrosylated depleted calstabin2 (FKBP12.6), resulting “leaky” channels diastolic SR leak. Inhibiting depletion complex channel stabilizer S107 (“rycal”) inhibited leak, aberrant depolarization isolated cardiomyocytes, prevented arrhythmias vivo. This suggests leak via due S-nitrosylation likely triggers Normalization RyR2-mediated prevents sudden