Accelerated cardiac remodeling in desmoplakin transgenic mice in response to endurance exercise is associated with perturbed Wnt/β-catenin signaling

BACKGROUND: Arrhythmogenic ventricular cardiomyopathy (AVC) is a frequent underlying cause for arrhythmias and sudden cardiac death especially during intense exercise. The mechanisms involved remain largely unknown. OBJECTIVE: To investigate how chronic endurance exercise contributes to desmoplakin (DSP) mutation-induced AVC pathogenesis. METHODS: Transgenic mice with overexpression of desmoplakin, wild-type (Tg-DSPWT) or the R2834H mutant (Tg-DSPR2834H) along with control non-transgenic (NTg) littermates were kept sedentary or exposed to a daily running regimen for 12 weeks. Cardiac function and morphology were analyzed using echocardiography, electrocardiography, histology, immunohistochemistry, RNA and protein analysis. RESULTS: At baseline, 4-week-old mice from all groups displayed normal cardiac function. When subjected to exercise, all mice retained normal cardiac function and left ventricular morphology; however, Tg-DSPR2834H mutants displayed right ventricular (RV) dilation and wall thinning, unlike NTg and Tg-DSPWT. The Tg-DSPR2834H hearts demonstrated focal fat infiltrations in RV and cytoplasmic aggregations consisting of desmoplakin, plakoglobin and connexin43. These aggregates coincided with disruption of the intercalated disks, intermediate filaments and microtubules. Though Tg-DSPR2834H mice already displayed high levels of p-GSK3-betaSer9 and p-AKT1Ser473 under sedentary conditions, decrease of nuclear GSK3-beta and AKT1 levels with reduced p-GSK3-betaSer9, p-AKT1Ser473, p-AKT1Ser308 and loss of nuclear JUP was apparent after exercise. In contrast, Tg-DSPWT showed up-regulation of p-AKT1Ser473, p-AKT1Ser308 and p-GSK3-betaSer9 in response to exercise. CONCLUSIONS: Our data suggest that endurance exercise accelerates AVC pathogenesis in Tg-DSPR2834H mice and this event is associated with perturbed AKT1 and GSK3-beta signaling. Our study suggests a potential mechanism-based approach to exercise management in patients with AVC.