Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study.

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
Abstract
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.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.We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.
Journal EUROPEAN HEART JOURNAL
ISSN 1522-9645
Published 21 Mar 2022
Volume 43
Issue 12
Pages 1251-1264
DOI 10.1093/eurheartj/ehab772
Type Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov't
Sponsorship