Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca2+ release

Cardiovasc Res. 2016 Aug 1;111(3):295-306. doi: 10.1093/cvr/cvw095. Epub 2016 May 8.


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.

Keywords: Arrhythmias; CPVT1; Ca2+ homeostasis; CaMKII; Exercise training.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Calcium / metabolism*
  • Calcium Signaling*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Disease Models, Animal
  • Exercise Therapy*
  • Female
  • Genetic Predisposition to Disease
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation, Missense
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Oxygen Consumption
  • Phenotype
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Running
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Sarcoplasmic Reticulum / enzymology
  • Tachycardia, Ventricular / enzymology
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / physiopathology
  • Tachycardia, Ventricular / prevention & control*
  • Time Factors


  • Antioxidants
  • Protein Kinase Inhibitors
  • Ryanodine Receptor Calcium Release Channel
  • ryanodine receptor 2. mouse
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia