Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 89, Issue -, Pages 177-184Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.11.009
Keywords
Duchenne muscular dystrophy; Oxidation; Phosphorylation; Reactive oxygen species; Ryanodine receptor type 2
Categories
Funding
- Muscular Dystrophy Association [186530]
- Mrs. Clifford Elder White Graham Endowed Research Fund
- NIH-NHLBI [HL089598, HL091947, HL117641, HL129570]
- American Heart Association [13EIA14560061]
- Juanita P. Quigley Endowed Chair in Cardiology
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [R01 AR061370]
- Mrs. Clifford Elder White Graham Endowed Research Fund Award
- Gillson Longenbaugh Foundation Award
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Background: Patients with Duchenne muscular dystrophy (DMD) are at risk of developing cardiomyopathy and cardiac arrhythmias. Studies in a mouse model of DMD revealed that enhanced sarcoplasmic reticulum (SR) Ca2+ leak contributes to the pathogenesis of cardiac dysfunction. In view of recent data suggesting the involvement of altered phosphorylation and oxidation of the cardiac ryanodine receptor (RyR2)/Ca2+ release channel, we hypothesized that inhibition of RyR2 phosphorylation in a mouse model of DMD can prevent SR Ca2+ leak by reducing RyR2 oxidation. Methods and results: Confocal Ca2+ imaging and single RyR2 channel recordings revealed that both inhibition of S2808 or S2814 phosphorylation, and inhibition of oxidation could normalize RyR2 activity in mdx mice. Moreover, Western blotting revealed that genetic inhibition of RyR2 phosphorylation at S2808 or S2814 reduced RyR2 oxidation. Production of reactive oxygen species (ROS) in myocytes from mdx mice was reduced by both inhibition of RyR2 phosphorylation or the ROS scavenger 2-mercaptopropionyl glycine (MPG). Finally, it was shown that ROS production in mdx mice is proportional to the activity of RyR2-mediated SR Ca2+ leak, and likely generated by Nox2. Conclusions: Increased ROS production in the hearts of mdx mice drives the progression of cardiac dysfunction. Inhibition of RyR2 phosphorylation can suppress SR Ca2+ leak in mdx mouse hearts in part by reducing RyR2 oxidation. (C) 2015 Elsevier Ltd. All rights reserved.
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