CALL FOR PAPERS Exercise Training in Cardiovascular Disease: Mechanisms and Outcomes Accelerated cardiac remodeling in desmoplakin transgenic mice in response to endurance exercise is associated with perturbed Wnt/ -catenin signaling
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چکیده
Martherus R, Jain R, Takagi K, Mendsaikhan U, Turdi S, Osinska H, James JF, Kramer K, Purevjav E, Towbin JA. Accelerated cardiac remodeling in desmoplakin transgenic mice in response to endurance exercise is associated with perturbed Wnt/ -catenin signaling. Am J Physiol Heart Circ Physiol 310: H174 –H187, 2016. First published November 6, 2015; doi:10.1152/ajpheart.00295.2015.—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 (TgDSP), or the R2834H mutant (Tg-DSP) 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 mutants displayed right ventricular (RV) dilation and wall thinning, unlike NTg and Tg-DSP. The Tg-DSP 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 mice already displayed high levels of p-GSK3Ser9 and p-AKT1 under sedentary conditions, decrease of nuclear GSK3and AKT1 levels with reduced p-GSK3, p-AKT1, and p-AKT1 and loss of nuclear junctional plakoglobin was apparent after exercise. In contrast, TgDSP showed upregulation of p-AKT1, p-AKT1, and p-GSK3Ser9 in response to exercise. Our data suggest that endurance exercise accelerates AVC pathogenesis in Tg-DSP mice and this event is associated with perturbed AKT1 and GSK3signaling. Our study suggests a potential mechanism-based approach to exercise management in patients with AVC.
منابع مشابه
Title : Effects of endurance exercise in arrhythmogenic ventricular cardiomyopathy : 1 accelerated cardiac remodeling in desmoplakin transgenic mice is associated with perturbed 2 Wnt / β - catenin signaling
Title: Effects of endurance exercise in arrhythmogenic ventricular cardiomyopathy: 1 accelerated cardiac remodeling in desmoplakin transgenic mice is associated with perturbed 2 Wnt/β-catenin signaling. 3 Running Head: Exercise Training and Arrhythmogenic Cardiomyopathy 4 5 Ruben Martherus, Rahul Jain*, Ken Takagi, Uzmee Mendsaikhan, Subat Turdi, Hanna 6 Osinska, Jeanne F. James, Kristen Kramer...
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