title: 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.
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Ruben
authors.initials: R
authors.lastname: Martherus
authors.affiliation: Department of Cardiology, Indiana University, Indianapolis, Indiana; and.
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Jikei University, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Uzmee
authors.initials: U
authors.lastname: Mendsaikhan
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Subat
authors.initials: S
authors.lastname: Turdi
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: James
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Kristen
authors.initials: K
authors.lastname: Kramer
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Enkhsaikhan
authors.initials: E
authors.lastname: Purevjav
authors.affiliation: Cardiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; jtowbin1@uthsc.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
mesh_terms: D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy*; D051180:Desmoplakins / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006334:Heart Function Tests; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000473:pathology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D012420:Running / Q000502:physiology; D057185:Sedentary Behavior; D014463:Ultrasonography; D051176:beta Catenin / Q000235:genetics* / Q000502:physiology*
chemical_list: C495267:CTNNB1 protein, mouse; D051180:Desmoplakins; C495295:Dsp protein, mouse; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: glycogen synthase kinase 3-β; protein kinase B