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

Ravinea Manotheepan, Tore K. Danielsen, Mani Sadredini, Mark E. Anderson, Cathrine R. Carlson, Stephan E. Lehnart, Ivar Sjaastad, Mathis K. Stokke

Research output: Contribution to journalArticlepeer-review

Abstract

Aims Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is caused by mutations in the cardiac ryanodine receptor (RyR2) that lead to disrupted Ca2+ 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 Ca2+ 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 Ca2+ sparks and waves, less diastolic Ca2+ leak from the sarcoplasmic reticulum, and lower phosphorylation levels at RyR2 sites associated with Ca2+-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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)295-306
Number of pages12
JournalCardiovascular research
Volume111
Issue number3
DOIs
StatePublished - Aug 1 2016

Keywords

  • Arrhythmias
  • CPVT1
  • Ca homeostasis
  • CaMKII
  • Exercise training

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca<sup>2+</sup> release'. Together they form a unique fingerprint.

Cite this