Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiomyopathy but significantly contributes to sudden cardiac death in young otherwise healthy patients, especially endurance athletes. 5-10% of patients with ARVC harbour mutations in the extracellular domains of the desmoglein (DSG) 2 gene. To assess the role of DSG2 in ARVC pathomechanism, mice lacking exons 4-6 of the endogenous DSG2 gene (DSG2mt) were generated. Homozygous DSG2mt/mice developed dilatation of ventricles and pronounced fibrosis. Heterozygous DSG2mt/wt mutants did not show such morphological alterations. Objective: To study whether physical exercise provokes a cardiac phenotype in DGSwt/mt mice, they were subjected to endurance training and compared with wild-type (WT) littermates. Methods/Results: Group swimming training sessions were performed 6 times a week, starting with 5 minutes and gradually incrementing to 90 minutes per day for 7 weeks. Echocardiography was performed before and after training, on mice anaesthetised with 2% isoflurane + oxygen, using a small animal ultrasound unit. Right ventricular (RV) diameters were increased in DSG2wt/mt both compared to pre-training, and compared to WT after training. Right ventricular function was also decreased after training compared to pre-training and compared to WT littermates (see table for values, *p<0.05, d= diastolic, s= systolic, lav= long axis view, sav= short axis view, FAC= fractional area shortening, HR= heart rate). Neither left ventricular diameters nor function differed between DSG2wt/mt and WT littermates. Electrophysiological studies in isolated Langendorff DSGwt/mt and Wt hearts from mice terminally anaesthetised with urethane (2mg/kg) showed comparable ventricular action potential duration and effective refractory periods. DSG2 mutation correlated with increased arrhythmia inducibility after endurance training. Ventricular arrhythmias were induced by a single extrastimulus during right ventricular stimulation in 5 of 8 DSG2wt/mt, but in none of the 7 WT hearts (p=0.03). In conclusion, endurance training reveals an ARVC-like phenotype in otherwise healthy and morphologically inconspicuous DSG2wt/mt mice presenting right ventricular dilation, decreased right ventricular contractility, and increased inducibility of ventricular arrhythmias during right ventricular pacing.