title: Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca2+ release.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Center for Heart Failure Research, University of Oslo, Oslo, Norway ravinea.manotheepan@medisin.uio.no.
authors.forename: Ravinea
authors.initials: R
authors.lastname: Manotheepan
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Tore K
authors.initials: TK
authors.lastname: Danielsen
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Mani
authors.initials: M
authors.lastname: Sadredini
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Cathrine R
authors.initials: CR
authors.lastname: Carlson
authors.affiliation: Clinic of Cardiology and Pulmonology, Heart Research Center Göttingen, Göttingen, Germany.
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Center for Heart Failure Research, University of Oslo, Oslo, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Center for Heart Failure Research, University of Oslo, Oslo, Norway Clinic for Internal Medicine, Lovisenberg Diakonale Hospital, Oslo, Norway.
authors.forename: Mathis K
authors.initials: MK
authors.lastname: Stokke
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D005081:Exercise Therapy; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D010101:Oxygen Consumption; D010641:Phenotype; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012420:Running; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D017180:Tachycardia, Ventricular / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000975:Antioxidants; D047428:Protein Kinase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Arrhythmias; CPVT1; Ca2+ homeostasis; CaMKII; Exercise training