In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 310, No. 2 ( 2016-01-15), p. H174-H187
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.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00295.2015
Language:
English
Publisher:
American Physiological Society
Publication Date:
2016
detail.hit.zdb_id:
1477308-9
SSG:
12
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