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

Abstract

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. The purpose of this study was to investigate how chronic endurance exercise contributes to desmoplakin (DSP) mutation-induced AVC pathogenesis. Transgenic mice with overexpression of desmoplakin, wild-type (Tg-DSP(WT)), or the R2834H mutant (Tg-DSP(R2834H)) along with control nontransgenic (NTg) littermates were kept sedentary or exposed to a daily running regimen for 12 wk. Cardiac function and morphology were analyzed using echocardiography, electrocardiography, histology, immunohistochemistry, RNA, and protein analysis. At baseline, 4-wk-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-DSP(R2834H) mutants displayed right ventricular (RV) dilation and wall thinning, unlike NTg and Tg-DSP(WT). The Tg-DSP(R2834H) hearts demonstrated focal fat infiltrations in RV and cytoplasmic aggregations consisting of desmoplakin, plakoglobin, and connexin 43. These aggregates coincided with disruption of the intercalated disks, intermediate filaments, and microtubules. Although Tg-DSP(R2834H) mice already displayed high levels of p-GSK3-β(Ser9) and p-AKT1(Ser473) under sedentary conditions, decrease of nuclear GSK3-β and AKT1 levels with reduced p-GSK3-β(Ser9), p-AKT1(Ser473), and p-AKT1(Ser308) and loss of nuclear junctional plakoglobin was apparent after exercise. In contrast, Tg-DSP(WT) showed upregulation of p-AKT1(Ser473), p-AKT1(Ser308), and p-GSK3-β(Ser9) in response to exercise. Our data suggest that endurance exercise accelerates AVC pathogenesis in Tg-DSP(R2834H) mice and this event is associated with perturbed AKT1 and GSK3-β signaling. Our study suggests a potential mechanism-based approach to exercise management in patients with AVC.

Are There Clinical Cardiac Complications From Too Much Exercise?

“…Similar findings were observed in plakophillin-2 (5) and desmoplakin deficient mice (16), suggesting that exercise training accelerates ARVD/C development in mutation carriers. Whether genotype to phenotype development is also accelerated in other genetic cardiac diseases such as hypertrophic cardiomyopathy and long QT syndrome is currently unknown.…”

Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

“…In contrast, 8x dyn-EHTs formed using DSPmut cardiomyocytes resulted in tissue lengthening and reduced contractile stress generation. Furthermore, in DSPmut tissues we found reduced amount and expression of desmosomes compared to control, which has also been observed in patients and small animal studies with desmosomal defects (5,71). Taken together, these findings suggest that 3D dynamic mechanical loading of EHTs may be better suited to investigate heart diseases with a cardiomyocytejunctional or cytoskeletal component.…”

“…As proof-of-concept, we chose to study ACM, where epidemiological data and animal models have indicated that enhanced mechanical loading, i.e. exercise, can accelerate disease progression in patients (5,(41)(42)(43)(44). To understand the impact of 2D versus 3D culture, we first investigated 2D monolayers of hiPSC-derived cardiomyocytes subjected to mechanical stretch.…”

“…For example, in arrhythmogenic cardiomyopathy (ACM), mechanical loading on heart muscle that leads to adaptive hypertrophy in healthy patients (i.e. exercise), can accelerate ACM disease progression and lead to ventricular dilation and reduced contractility (4,5). This interplay between patient-specific genetic background and mechanical force is likely critical to understanding a range of cardiac disease states.…”

Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy

“…Finally, Wnt pathway perturbation, due to reduced AKT and GSK3β activation, has been recently associated to exercise-induced acceleration of AC phenotype in mice overexpressing a mutant form of desmoplakin and exposed to a daily running [ 95 ]. The identification of a Wnt pathway activator as the molecule that can rescue the features of the AC phenotype both in a zebrafish and in additional mouse models [ 96 , 97 ] strongly supports the association between AC and suppression of this signaling pathway.…”