PDF(Pubmed)
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 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.
摘要：
背景：TMEM43/LUMAp.S358L突变导致心律失常性心肌病，称为ARVC5，这是一种具有室性心律失常高风险的完全渗透疾病，猝死和心力衰竭.男性和剧烈运动独立预测有害结果。我们的系统遗传学分析揭示了Tmem43对与小肠脂质吸收升高相关的心脏和代谢途径的重要性。这项研究试图描绘性别特异性心脏，肠,和体内代谢表型，并研究S358L突变的潜在病理生理机制。
方法：系列超声心动图，体表心电图(ECG),跑步机跑步和身体EchoMRI已用于敲入杂合子（Tmem43WT/S358L），纯合(Tmem43S358L)和野生型(Tmem43WT)同窝小鼠。电子显微镜,组织学,免疫组织化学，转录组，和蛋白质分析已经在心脏和肠道组织中进行。
结果：在3个月大的Tmem43S358L和6个月大的Tmem43WT/S358L突变体中出现明显的收缩功能障碍。两种突变品系在6个月大时表现出对急性压力的不耐受，心律失常,纤维脂肪浸润，和心肌亚细胞异常。微阵列分析发现LV和RV心肌之间显著差异表达基因。突变体显示PPARG活性降低，心脏中Tmem43和b-catenin表达显著降低，而JUP易位到突变心肌细胞的细胞核中。相反，细长的绒毛，脂肪渗透,和肠道上皮增殖标志物的过度表达，b-catenin和Ki-67在突变体的小肠中很明显。
结论：我们定义了Tmem43S358L诱导的对心脏和肠道稳态的病理作用，其直接干扰了WNT-b-catenin和PPARG信号传导，从而有助于ARVC5病理生理学。结果表明，突变携带者的心脏代谢评估对于预测性和个性化护理可能很重要。
方法：系列超声心动图，体表心电图(ECG),跑步机跑步和身体EchoMRI已用于敲入杂合子（Tmem43WT/S358L），纯合(Tmem43S358L)和野生型(Tmem43WT)同窝小鼠。电子显微镜,组织学,免疫组织化学，转录组，和蛋白质分析已经在心脏和肠道组织中进行。
结果：在3个月大的Tmem43S358L和6个月大的Tmem43WT/S358L突变体中出现明显的收缩功能障碍。两种突变品系在6个月大时表现出对急性压力的不耐受，心律失常,纤维脂肪浸润，和心肌亚细胞异常。微阵列分析发现LV和RV心肌之间显著差异表达基因。突变体显示PPARG活性降低，心脏中Tmem43和b-catenin表达显著降低，而JUP易位到突变心肌细胞的细胞核中。相反，细长的绒毛，脂肪渗透,和肠道上皮增殖标志物的过度表达，b-catenin和Ki-67在突变体的小肠中很明显。
结论：我们定义了Tmem43S358L诱导的对心脏和肠道稳态的病理作用，其直接干扰了WNT-b-catenin和PPARG信号传导，从而有助于ARVC5病理生理学。结果表明，突变携带者的心脏代谢评估对于预测性和个性化护理可能很重要。
