Genetic Inactivation of β-Catenin Attenuates and Its Activation Aggravates Desmoplakin Cardiomyopathy

• DOI: 10.1101/2023.03.02.530831
• Publication Date: 2023-03-07T06:40:13Z
• Authors: Melis Olcum; Siyang Fan; Leila Rouhi; Sirisha Cheedipudi; Benjamin Cathcart; Hyun-Hwan Jeong; Zhongming Zhao; Priyatansh Gurha; Ali J. Marian
• Keywords: Desmoplakin; Plakoglobin; Beta-catenin

ABSTRACT Aim Mutations in the DSP gene encoding desmoplakin, a constituent of desmosomes at intercalated discs (IDs), cause phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated (DCM). It is typically characterized by biventricular enlargement dysfunction, severe myocardial fibrosis, cell death, arrhythmias. The canonical WNT (cWNT)/β-catenin signaling pathway implicated pathogenesis ACM. Given β-catenin, an indispensable co-transcriptional regulator cWNT pathway, also member IDs, we genetically inactivated or activated β-catenin to determine its role desmoplakin cardiomyopathy. Methods Results Dsp was conditionally deleted cardiac myocytes concomitant with genetic inactivation activation using tamoxifen-inducible MerCreMer mice. Inactivation were achieved upon deletion transcriptional domain degrons, respectively. Analysis transcripts proteins showed marked dysregulation cWNT/β-catenin DSP-deficient mouse ( Myh6-Mcm Tam : F/F ), as indicated increased expression targets along inhibitors isoforms key co-effectors. Genetic mice prolonged survival, improved function, reduced arrhythmias, attenuated death caused apoptosis, necroptosis, pyroptosis, i.e., PANoptosis, whereas had opposite effects. associated partial restoration suppressed genes involved OXPHOS, has effect. beneficial effects independent changes transcript levels target genes. Conclusion markedly dysregulated from model DC. partly through recovery OXPHOS deleterious findings suggest suppression might be desmoplakin-cardiomyopathy. Summary cardiomyopathy, part oxidative phosphorylation, deleterious.