Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca 2+ release. Issue 3 (8th May 2016)

• Record Type: Journal Article
• Authors: Manotheepan, Ravinea; Danielsen, Tore K.; Sadredini, Mani; Anderson, Mark E.; Carlson, Cathrine R.; Lehnart, Stephan E.; Sjaastad, Ivar; Stokke, Mathis K.
• Is Part Of: Cardiovascular research. Volume 111:Issue 3(2016)
• Page Start: 295
• Page End: 306
• Publication Date: 2016-05-08
• Subjects: Arrhythmias -- CPVT1 -- Exercise training -- Ca 2+ homeostasis -- CaMKII; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvw095
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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 (VO 2max ) and 2 min active rest periods at 60%. VO 2max 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.