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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

The failing heart is energy-starved and redox imbalanced. Understanding how, and where cardiac energetic and redox alterations intersect in the failing heart are paramount to understanding and treating heart failure (HF). Creatine kinase (CK) is the major myocardial energy reserve reaction and ATP buffer with isozymes in the cytosol (CK-M) and mitochondria (Mt-CK). CK activity is reduced in human HF and following transverse aortic constriction (TAC). Mt-CK is an octamer particularly prone to oxidative modifications. It is not known whether HF changes in Mt-CK contribute to alter myocardial redox state in HF. We found that, in failing TAC WT hearts, a marked rise in reactive oxygen species (ROS) emission occurs (+93%, n=13, p