The TMEM43 S358L mutation affects cardiac, small intestine, and metabolic homeostasis in a knock-in mouse model.
Buyan-Ochir OrgilUndral MunkhsaikhanJoseph F PierreNing LiFuyi XuNeely R AlbersonJason N JohnsonGlenn T WetzelBastiaan J D BoukensLu LuJeffrey A TowbinEnkhsaikhan PurevjavPublished in: American journal of physiology. Heart and circulatory physiology (2023)
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 (Tmem43 WT/S358L ), homozygous (Tmem43 S358L ), and wildtype (Tmem43 WT ) 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 Tmem43 S358L and 6-mo-old Tmem43 WT/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 β-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, β-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-β-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. NEW & NOTEWORTHY This manuscript describes the findings of our investigation of cardiac, small intestine, and metabolic features 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 subjects carrying TMEM43 mutation.
Keyphrases
- left ventricular
- heart failure
- mouse model
- hypertrophic cardiomyopathy
- cell proliferation
- acute myocardial infarction
- cardiac resynchronization therapy
- epithelial mesenchymal transition
- healthcare
- magnetic resonance
- wild type
- high intensity
- dna methylation
- metabolic syndrome
- intensive care unit
- gene expression
- transcription factor
- aortic stenosis
- palliative care
- mental health
- small molecule
- early onset
- mycobacterium tuberculosis
- computed tomography
- fatty acid
- hepatitis b virus
- oxidative stress
- stem cells
- skeletal muscle
- squamous cell carcinoma
- single cell
- magnetic resonance imaging
- type diabetes
- heat stress
- acute respiratory distress syndrome
- diabetic rats
- aortic dissection
- extracorporeal membrane oxygenation
- contrast enhanced