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

Abstract

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