The Tmem43-S358l Mutation Affects Cardiac and Small Intestine Homeostasis Contributing to Arvc5 Pathogenesis in Vivo

Objectives: This study sought to delineate clinical phenotype and investigate pathophysiological mechanisms of arrhythmogenic right ventricular cardiomyopathy (ARVC5) in vivo.Background: Mutation p.S358L in TMEM43/LUMA causes ARVC5, a fully penetrant gender- and exercise-dependent disease. Exact pathophysiological mechanisms of ARVC5 remain incomplete and controversial. Methods: Knock-in Tmem43S358L mice were generated using conventional targeting. Assessment of cardiac and intestinal phenotypes, transcriptome and protein analysis were performed. Results: Onset of systolic dysfunction and rhythm asymmetry was apparent in 3-month-old homozygote mutants. Heterozygote 6-month-old mutants displayed systolic dysfunction as well. Biventricular myocardial fibro-fatty infiltration and subcellular abnormalities were found in both mutants, while acute stress caused ventricular tachycardia and death in homozygotes. Microarray revealed that WNT-b-catenin and PPARG signaling-associated genes were differentially expressed between LV and RV. Tmem43S358L mutants displayed significantly reduced PPARG activities and downregulation of PPARG-downstream metabolic genes in the heart. Expression of b-catenin were significantly reduced, while JUP was translocated into nuclei of mutant cardiomyocytes. Conversely in small intestine, b-catenin and PPARG-associated genes responsible for cholesterol, bile acid, and lipid transport were upregulated in Tmem43S358L mutants resulting in elevated lipids absorption, hyperlipidemia, and reciprocal fecal lipids reduction. These abnormalities were associated with elongated villi, fatty infiltrations, and gut epithelial proliferation markers in small intestine. Conclusions: We defined novel distinct effects of the TMEM43-S358L mutation on small intestine homeostasis in addition to cardiac damage. Tmem43-S358L perturbs PPARG and WNT-b-catenin signaling in the heart as well as in intestine, elevating lipids absorption from gut lumen whereby triggering ACM pathophysiology.