Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study
Year: 2021
Type: article
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.
Source: European Heart Journal
Authors: Marina Cerrone, Grecia M Marrón-Liñares, Chantal J M van Opbergen, Sarah Costa, Mimount Bourfiss, Marta Pérez-Hernández, Florencia Schlamp, Fabian Sanchis-Gomar, Kabir Malkani, Kamelia Drenkova, Mingliang Zhang, Xianming Lin, Adriana Heguy, Birgitta K Velthuis, Niek H J Prakken, Andre LaGerche, Hugh Calkins, Cynthia A James, Anneline S J M Te Riele, Mario Delmar
Institutions: New York University, University Medical Center Utrecht, Netherlands Heart Institute, Universitat de València, INCLIVA Health Research Institute, University Medical Center Groningen, University of Groningen, Baker Heart and Diabetes Institute, St Vincent's Hospital Melbourne, Johns Hopkins University, Johns Hopkins Hospital
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: American Heart Association, Heart Rhythm Society, Johns Hopkins University, Fondation Leducq, Hartstichting, Universitair Medisch Centrum Utrecht, Peter French Memorial Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences
Awards: Role of PKP2 in epicardial structure and function, G1903264167, G3115662587, Exercise-induced maladaptive hypertrophy in PKP2-deficient mice: Implications to the pathophysiology of ARVC, G4648709136, Role of desmosomes in cardiac electrical function, G5693982146, The sodium channel ecosystem in the adult ventricular myocyte, EXOGENOUS FACTORS IN THE ARRHYTHMOGENIC CARDIOMYOPATHY PHENOTYPE, G749197152, G7813502019, Johns Hopkins Institute for Clinical and Translational Research, Molecular Atlas of the Cardiac Intercalated Disc
OpenAlex ID: W4200527283