Exercise accelerated cardiac dysfunction in PKP2-deficient mice, and human athletes carrying PKP2 mutations had reduced cardiac dimensions compared to matched controls.
Does endurance training accelerate cardiomyopathy progression in subjects with plakophilin-2 (PKP2) deficiency?
Exercise accelerates the progression of arrhythmogenic right ventricular cardiomyopathy in the presence of PKP2 mutations by challenging the cardiomyocyte desmosomal reserve.
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.
Cerrone et al. (Fri,) conducted a other in Arrhythmogenic right ventricular cardiomyopathy. Endurance training and PKP2 mutation vs. Sedentary state and matched controls was evaluated on Transcriptomic changes, cardiac function, and cardiac dimensions. Exercise accelerated cardiac dysfunction in PKP2-deficient mice, and human athletes carrying PKP2 mutations had reduced cardiac dimensions compared to matched controls.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: