Ravinea Manotheepan1, Tore K Danielsen2, Mani Sadredini2, Mark E Anderson3, Cathrine R Carlson2, Stephan E Lehnart4, Ivar Sjaastad2, Mathis K Stokke5. 1. 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. 2. Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway Center for Heart Failure Research, University of Oslo, Oslo, Norway. 3. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4. Clinic of Cardiology and Pulmonology, Heart Research Center Göttingen, Göttingen, Germany. 5. 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.
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 (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. Published on behalf of the European Society of Cardiology. All rights reserved.
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-R2474Smice (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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Mathis K Stokke; Karina Hougen; Ivar Sjaastad; William E Louch; Sarah J Briston; Ulla H Enger; Kristin B Andersson; Geir Christensen; David A Eisner; Ole M Sejersted; Andrew W Trafford Journal: Cardiovasc Res Date: 2009-12-17 Impact factor: 10.787
Authors: Efrat Kurtzwald-Josefson; Edith Hochhauser; Guy Katz; Eyal Porat; Jonathan G Seidman; Christine E Seidman; Yelena Chepurko; Asher Shainberg; Michael Eldar; Michael Arad Journal: J Appl Physiol (1985) Date: 2012-10-04
Authors: Tore K Danielsen; Ravinea Manotheepan; Mani Sadredini; Ida S Leren; Andrew G Edwards; Kevin P Vincent; Stephan E Lehnart; Ole M Sejersted; Ivar Sjaastad; Kristina H Haugaa; Mathis K Stokke Journal: PLoS One Date: 2018-11-06 Impact factor: 3.240