Abstract 20589: Exercise and Mitochondrial Respiration in Mice with Arrhythmogenic Cardiomyopathy

Abstract

Incomplete penetrance of Arrhythmogenic Cardiomyopathy (AC) suggests environmental factors, such as exercise, influence disease progression. We have previously demonstrated that increased PPARγ contributes to apoptosis and fat deposition in a cellular model of AC. Therefore, we examined the effects of exercise training in a mouse model of AC (knock-in desmoglein-2 mutant). Desmoglein-2 homozygous (Dsg2mut/mut, n=12), heterozygous (Dsg2mut/+, n=11) and WT (n=9) mice were forced to swim train at 5 weeks of age (10min/day increments) and by 7 weeks mice swam 90min/day, 5 days/week. At 16 weeks of age echo- and electrocardiographic, mitochondrial, histological, gene expression and protein analysis were performed. Non-exercised Dsg2mut/mut mice showed redistribution of Cx43, Dsg2, GSK3β and nuclear PKG, increased apoptosis and reduced ejection fraction (EF, p<0.001) and fractional shortening (FS, p<0.01) compared to WT controls by 16 weeks of age. Additionally, by 6 weeks of age Dsg2mut/mut mice (n=3/group) demonstrated reduced carnitine-palmitoyltransferase-1 (p=0.029), increased PPARα (p=0.05), FABP4 (p=0.05) and CEBPα (p=0.04) gene expression and decreased State 3 respiration with Complex I substrates (p=0.01) compared to WT mice. In exercise studies, 50% (6/12) of Dsg2mut/mut mice survived to 16 weeks of age, whereas 6 died suddenly while swimming (mean time of death 19.5 ± 3.88 days post-swimming, p=0.03). Exercised Dsg2mut/mut mice (n=6) showed reduced EF and FS compared to Dsg2mut/+ (n=10) and WT mice (n=8, p<0.001 for all comparisons). Dsg2mut/mut mice had longer mean QRS complex duration (23.9 ± 0.03 ms, p=0.05) and isovolumetric relaxation time (IVRT: 31.3 ± 3.5 ms, p=0.02) compared to Dsg2mut/+ and WT mice (n=3/group; QRS: 23.4 ± 0.03 ms, 19.4 ± 0.02 ms; IVRT: 23.8 ± 0.8 ms, 23.3 ± 1.9 ms, respectively). Furthermore, Dsg2mut/mut mice exhibit higher mitochondrial membrane potential (n=3/group, p=0.03) compared to Dsg2mut/+ and WT mice, and a trend towards increased pyruvate oxidation rate and decreased beta-oxidation rate. These data show that Dsg2mut/mut mice are at risk of arrhythmic fatality and demonstrate glycolytic-dominant respiration during exercise.