The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model

作者：Orgil, Buyan-Ochir; Munkhsaikhan, Undral; Pierre, Joseph F.; Li, Ning; Xu, Fuyi; Alberson, Neely R.; Johnson, Jason N.; Wetzel, Glenn T.; Boukens, Bastiaan J. D.; Lu, Lu; Towbin, Jeffrey A.; Purevjav, Enkhsaikhan^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2023, 324(6): H866-H880.

DOI：10.1152/ajpheart.00712.2022

• arrhythmogenic cardiomyopathy
• ARVC5
• PPARG
• TMEM43
• LUMA
• Wnt-b-catenin

The transmembrane protein 43 (TMEM43/LUMA) p.S358L mutation causes arrhythmogenic cardiomyopathy named as ARVC5, a fully penetrant disease with high risk of ventricular arrhythmias, sudden death, and heart failure. Male gender and vigorous exer-cise independently predicted deleterious outcome. Our systems genetics analysis revealed the importance of Tmem43 for car-diac and metabolic pathways associated with elevated lipid absorption from small intestine. This study sought to delineate gender-specific cardiac, intestinal, and metabolic phenotypes in vivo and investigate underlying pathophysiological mechanisms of S358L mutation. Serial echocardiography, surface electrocardiography (ECG), treadmill running, and body EchoMRI have been used in knock-in heterozygous (Tmem43WT/S358L), homozygous (Tmem43S358L), and wildtype (Tmem43WT) littermate mice. Electron microscopy, histology, immunohistochemistry, transcriptome, and protein analysis have been performed in cardiac and intestinal tissues. Systolic dysfunction was apparent in 3-mo-old Tmem43S358L and 6-mo-old Tmem43WT/S358L mutants. Both mu-tant lines displayed intolerance to acute stress at 6 mo of age, arrhythmias, fibro-fatty infiltration, and subcellular abnormalities in the myocardium. Microarray analysis found significantly differentially expressed genes between left ventricular (LV) and right ven-tricular (RV) myocardium. Mutants displayed diminished PPARG activities and significantly reduced TMEM43 and b-catenin expression in the heart, whereas junctional plakoglobin (JUP) translocated into nuclei of mutant cardiomyocytes. Conversely, elongated villi, fatty infiltration, and overexpression of gut epithelial proliferation markers, b-catenin and Ki-67, were evident in small intestine of mutants. We defined Tmem43 S358L-induced pathological effects on cardiac and intestinal homeostasis via distinctly disturbed WNT-b-catenin and PPARG signaling thereby contributing to ARVC5 pathophysiology. Results suggest that cardi-ometabolic assessment in mutation carriers may be important for predictive and personalized care.NEW & NOTEWORTHY This manuscript describes the findings of our investigation of cardiac, small intestine, and metabolic fea-tures of Tmem43-S358L mouse model. By investigating interorgan pathologies, we uncovered multiple mechanisms of the S358L-induced disease, and these unique mechanisms likely appear to contribute to the disease pathogenesis. We hope our findings are important and novel and open new avenues in the hunting for additional diagnostic and therapeutic targets in sub-jects carrying TMEM43 mutation.

• 单位
  哈尔滨医科大学