Marina Cerrone1, Grecia M Marrón-Liñares1, Chantal J M van Opbergen1, Sarah Costa2, Mimount Bourfiss3, Marta Pérez-Hernández1, Florencia Schlamp1, Fabian Sanchis-Gomar4, Kabir Malkani1, Kamelia Drenkova1, Mingliang Zhang1, Xianming Lin1, Adriana Heguy5, Birgitta K Velthuis6, Niek H J Prakken7, Andre LaGerche8, Hugh Calkins9, Cynthia A James9, Anneline S J M Te Riele3, Mario Delmar1. 1. The 'Leon Charney' Division of Cardiology, New York University Grossmann School of Medicine, 435 East 30th Street, NSB 707, New York, NY 10016, USA. 2. Division of Cardiology, University Heart Center Zurich, Rämistrasse 100, Zurich CH-8091, Switzerland. 3. Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht and The Netherlands Heart Institute, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. 4. Department of Physiology, Faculty of Medicine, University of Valencia and INCLIVA Biomedical Research Institute, C. de Menéndez y Pelayo, 4, 46010 Valencia, Spain. 5. Genome Technology Center, Department of Pathology, New York University Grossmann School of Medicine, 550 First Avenue, New York, NY 10016, USA. 6. Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. 7. Department of Radiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. 8. Clinical Research Domain, Baker Heart and Diabetes Institute, 75 Commercial Rd, Melbourne VIC 3004, Australia and National Centre for Sports Cardiology, St Vincent's Hospital Melbourne, Building C, 41 Victoria Parade, Fitzroy VIC 3065, Australia. 9. Division of Cardiology, Johns Hopkins Hospital, 1800 Orleans St, Baltimore, MD 21287, USA.
Abstract
AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy. Published on behalf of the European Society of Cardiology. All rights reserved.
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