Key result
A 2-week interval treadmill exercise training protocol reduced ventricular tachycardia episodes in CPVT1-mutant mice through lower CaMKII-dependent phosphorylation of RyR2.
Why the study?
Does interval treadmill exercise training reduce ventricular tachycardia in mice with the CPVT1-causative Ryr2-R2474S mutation?
Does interval treadmill exercise training reduce ventricular tachycardia in mice with the CPVT1-causative Ryr2-R2474S mutation?
In a mouse model of CPVT1, interval exercise training reduced ventricular tachycardia episodes by decreasing oxidized CaMKII and subsequent RyR2 phosphorylation.
Answers are grounded in this paper and cite their sources.
Should not yet alter CPVT care; leaves open translation of exercise benefits from CPVT1 mice to patients.
AIMS: Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is caused by mutations in the cardiac ryanodine receptor (RyR2) that lead to disrupted Ca(2+) handling in cardiomyocytes and ventricular tachycardia. The aim of this study was to test whether exercise training could reduce the propensity for arrhythmias in mice with the CPVT1-causative missense mutation Ryr2-R2474S by restoring normal Ca(2+) handling. METHODS AND RESULTS: Ryr2-R2474S mice (RyR-RS) performed a 2 week interval treadmill exercise training protocol. Each exercise session comprised five 8 min intervals at 80-90% of the running speed at maximal oxygen uptake (VO2max) and 2 min active rest periods at 60%. VO2max increased by 10 ± 2% in exercise trained RyR-RS (ET), while no changes were found in sedentary controls (SED). RyR-RS ET showed fewer episodes of ventricular tachycardia compared with RyR-RS SED, coinciding with fewer Ca(2+) sparks and waves, less diastolic Ca(2+) leak from the sarcoplasmic reticulum, and lower phosphorylation levels at RyR2 sites associated with Ca(2) (+)-calmodulin-dependent kinase type II (CaMKII) compared with RyR-RS SED. The CaMKII inhibitor autocamtide-2-related inhibitory peptide and also the antioxidant N-acetyl-l-cysteine reduced Ca(2+) wave frequency in RyR-RS equally to exercise training. Protein analysis as well as functional data indicated a mechanism depending on reduced levels of oxidized CaMKII after exercise training. Two weeks of detraining reversed the beneficial effects of the interval treadmill exercise training protocol in RyR-RS ET. CONCLUSION: Long-term effects of interval treadmill exercise training reduce ventricular tachycardia episodes in mice with a CPVT1-causative Ryr2 mutation through lower CaMKII-dependent phosphorylation of RyR2.
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Manotheepan et al. (2016) studied Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1). Interval treadmill exercise training vs. Sedentary controls was evaluated on Episodes of ventricular tachycardia and Ca2+ handling. A 2-week interval treadmill exercise training protocol reduced ventricular tachycardia episodes in CPVT1-mutant mice through lower CaMKII-dependent phosphorylation of RyR2.
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