Genetic Activation and Suppression of the Canonical WNT Pathway in Cardiac Myocyte-Specific Dsp Deficient Mouse Model of Arrhythmogenic Cardiomyopathy

The cWNT pathway has been implicated in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), including in cardiac dysfunction, apoptosis, and fibro-adipogenesis, the latter being the histological hallmark of ACM. The study was designed to determine effects of genetic activation or suppression of cWNT in a mouse model of arrhythmogenic cardiomyopathy. The data show that activation of the cWNT in ACM deleterious whereas it suppression is benefiial. The cWNT signaling pawathway was activated or suppressed post-nataly (P14) using tamoxifen-inducible cre and floxed beta catenin gene while concomittantly deleting the Dsp deficiency, all specificially in cardiac myocytes. The experimental groups include wild type (WT), Myh6-MerCreMer, , Myh6-MCM:DspF/F, Myh6-MCM:Ctnnb1GoF (Gain of function) , Myh6-MCM:Ctnnb1LoF (Loss of function), Myh6-MCM:DspF/F:Ctnnb1LoF , and Myh6-MCM:DspF/F:Ctnnb1GoF/F mice. Phenotypic characterization and myocyte RNA sequencing were performed at 4 weeks of age.