Altered Thioredoxin-AIF Crosstalk Underlies Exercise-induced Cardiac Cell Death in Arrhythmogenic Cardiomyopathy

Exercise increases arrhythmic risk and sudden cardiac death (SCD) in arrhythmogenic cardiomyopathy (ACM) subjects via unknown mechanisms. Exercise increases reactive oxygen species (ROS) generation. Yet antioxidant defenses, such as the thioredoxin (Trx) system effectively buffer ROS, preventing cardiac oxidative damage. Desmoglein-2 (DSG2) mutations are commonly associated to ACM, accordingly we generated a knock-in ACM mouse model bearing a mutation in murine Dsg2 (Dsg2mut/mut). Then, we subjected WT and Dsg2mut/mut mice to a 10 week swimming protocol, monitoring cardiac function, and terminally assessing cardiac tissue Trx1/2 protein levels and ROS production by EPR. Of note, only 60% (15/25) of Dsg2mut/mutmice survived to exercise end-point, compared to WT mice (91%, 20/22, p=0.008). No SCD occurred in age-matched sedentary mice. While sedentary and exercised Dsg2mut/mut mice (EF: 57±4 vs 84±0.4% in WT; n≥14/cohort, P