title: Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médical U637, Physiopathologie Cardiovasculaire, F-34295 Montpellier, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Cécile
authors.initials: C
authors.lastname: Cassan
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.forename: Stefan
authors.initials: S
authors.lastname: Matecki
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism
chemical_list: D002118:Calcium; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse