Maintenance of Energy Metabolism Is an Integral Part of Plakophilin-2 and Desmosome Functions

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Alterations in the desmosome gene plakophilin-2 (PKP2) lead to compromised contractility and electrical instability of cardiomyocytes. In this study, we utilized ARVC mouse and human induced pluripotent stem cell-derived cardiomyocyte models to confirm impaired energy metabolism that concorded with the human data. Our results supported an intrinsic cellular link between PKP2 and energy metabolism. TN-401-mediated PKP2 expression improved mitochondrial and glycolytic energetics and rescued cardiomyocyte functions that are dictated by mechanical and structural integrity of desmosome. Therefore, maintaining energy metabolism of cardiomyocytes is an integral part of PKP2 and desmosome functions, adding a new layer of understanding to ARVC disease mechanism.