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Published on: December 22, 2023
Crosstalk between RyR2 oxidation and phosphorylation contributes to cardiac dysfunction in mice with Duchenne
Qiongling Wang1, Wei Wang1, Guoliang Wang1
1Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
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) Ca(2+) 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)/Ca(2+) release channel, we hypothesized that inhibition of RyR2 phosphorylation in a mouse model of DMD can prevent SR Ca(2+) leak by reducing RyR2 oxidation.
Methods And Results:
Confocal Ca(2+) 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 Ca(2+) 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 Ca(2+) leak in mdx mouse hearts in part by reducing RyR2 oxidation.
Insights
In Duchenne muscular dystrophy (DMD) mouse models, inhibiting ryanodine receptor (RyR2) phosphorylation reduces calcium (Ca2+) leak and oxidative stress, preventing cardiac dysfunction and arrhythmias.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) patients are susceptible to cardiomyopathy and arrhythmias.
- Enhanced sarcoplasmic reticulum (SR) Ca2+ leak contributes to cardiac dysfunction in DMD.
- Altered phosphorylation and oxidation of the cardiac ryanodine receptor (RyR2) are implicated.
Purpose of the Study:
- To investigate if inhibiting RyR2 phosphorylation can prevent SR Ca2+ leak in a mouse model of DMD.
- To determine if reduced RyR2 phosphorylation decreases RyR2 oxidation.
Main Methods:
- Confocal Ca2+ imaging and single RyR2 channel recordings in mdx mice.
- Western blotting to assess RyR2 phosphorylation and oxidation.
- Measurement of reactive oxygen species (ROS) production in myocytes.
Main Results:
- Inhibiting RyR2 phosphorylation at S2808 or S2814, or inhibiting oxidation, normalized RyR2 activity in mdx mice.
- Genetic inhibition of RyR2 phosphorylation reduced RyR2 oxidation.
- ROS production in mdx myocytes decreased with RyR2 phosphorylation inhibition or ROS scavenger treatment.
- ROS production correlated with RyR2-mediated SR Ca2+ leak, likely via Nox2.
Conclusions:
- Increased ROS production drives cardiac dysfunction in mdx mouse hearts.
- Inhibiting RyR2 phosphorylation suppresses SR Ca2+ leak by reducing RyR2 oxidation in mdx hearts.
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