Abstract 12612: Exercise Training Reduces Ca2+-Calmodulin-dependent Protein Kinase Type II Dependent Phosphorylation of the Cardiac Ryanodine Receptor and Ca2+ Leak From the Sarcoplasmic Reticulum in Mice With Mutant Cardiac Ryanodine Receptor 2
Introduction: Catecholaminergic Polymorphic Ventricular Tachycardia caused by RyR2 mutations predisposes to stress-induced arrhythmias due to disrupted Ca2+ handling in ventricular cardiomyocytes. We tested the effect of exercise training (ET) on Ca2+ handling in mice with a human RyR2 mutation (RyR-R2474S).
Methods and results: C57BI6 mice were employed to test the efficacy of a two week ET protocol, comprising five eight-minute intervals at 80-90 % of the running speed at maximal oxygen uptake (VO2max, ml/kg/min), and two-minute active rest periods at 60 %. ET mice (C57BI6-ET) increased VO2max by 7 % compared to baseline (152±2 vs. 142±2, P≤0.05), while no change was found in sedentary mice (C57BI6-SED) (139±1 vs. 140±1). Autophosphorylated CaMKII was reduced in C57BI6-ET compared to C57BI6-SED (52±9 vs. 100±8 %, P≤0.05), as was CaMKII-dependent Ser2814-phosphorylated RyR2 (37±12 vs. 100±15 %, P≤0.05). Thr17-phosphorylated phospholamban was unaltered (69±18 vs. 100±5). Contrary, C57BI6-ET exhibited increased PKA-dependent Ser16-phosphorylated phospholamban (140±11 vs. 100±9 %, P≤0.05) but no change in Ser2808-phosphorylated RyR2.
ET RyR2-R2474S mice (RyR2-RS-ET) increased VO2max by 10±3 % compared to baseline (135±3 vs. 123±2, P≤0.05), while VO2max in RyR2-RS-SED decreased by 5±2 % (124±2 vs. 131±3, P≤0.05). RyR2-RS-ET compared to RyR2-RS SED showed decreased levels of Ser2814-phosphorylated RyR2 (38±3 vs. 100±13 %, P≤0.05), but no alterations in Thr17-phosphorylated phospholamban. Contrary, RyR-RS-ET mice exhibited increased levels of Ser2808-phosphorylated RyR2 (150±14 vs. 100±16 %, P≤0.05) and Ser16-phosphorylated phospholamban (167±25 vs. 100±14 %, P≤0.05). Whole-cell Ca2+ imaging in ventricular cardiomyocytes showed decreased SR Ca2+ leak normalized to SR Ca2+ content in RyR2-RS-ET vs. SED (F/F0: 11±2 vs. 25±5, P≤0.05).
Conclusion: Two weeks of high-intensity exercise training in C57BI6-WT and RyR2-RS increased VO2max, decreased CaMKII-dependent phosphorylation of RyR2, and reduced SR Ca2+ leak. These effects of ET may decrease the propensity for arrhythmias in CPVT.
- Arrhythmias, treatment of
- Gene mutations
- Excitation-contraction coupling (ECC)
- © 2013 by American Heart Association, Inc.