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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 exercise independently predicted deleterious outcome. Our systems genetics analysis revealed the importance of Tmem43 for cardiac 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 mutant 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 ventricular (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 cardiometabolic assessment in mutation carriers may be important for predictive and personalized care.

Original languageEnglish (US)
Pages (from-to)H866-H880
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume324
Issue number6
DOIs
StatePublished - Jun 2023
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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