Comprehensive Heart Failure Center, Department of Internal Medicine I, University Hospital Würzburg, 97080 Würzburg, Germany.
Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany.
Int J Mol Sci. 2022 Aug 23;23(17):9530. doi: 10.3390/ijms23179530.
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (TMEM43). The disease is characterized by myocyte loss and fibro-fatty replacement, leading to life-threatening ventricular arrhythmias and sudden cardiac death. However, the role of TMEM43 in the pathogenesis of ACM remains poorly understood. In this study, we generated cardiomyocyte-restricted transgenic zebrafish lines that overexpress eGFP-linked full-length human wild-type (WT) TMEM43 and two genetic variants (c.1073C>T, p.S358L; c.332C>T, p.P111L) using the Tol2-system. Overexpression of WT and p.P111L-mutant TMEM43 was associated with transcriptional activation of the mTOR pathway and ribosome biogenesis, and resulted in enlarged hearts with cardiomyocyte hypertrophy. Intriguingly, mutant p.S358L TMEM43 was found to be unstable and partially redistributed into the cytoplasm in embryonic and adult hearts. Moreover, both TMEM43 variants displayed cardiac morphological defects at juvenile stages and ultrastructural changes within the myocardium, accompanied by dysregulated gene expression profiles in adulthood. Finally, CRISPR/Cas9 mutants demonstrated an age-dependent cardiac phenotype characterized by heart enlargement in adulthood. In conclusion, our findings suggest ultrastructural remodeling and transcriptomic alterations underlying the development of structural and functional cardiac defects in TMEM43-associated cardiomyopathy.
致心律失常性心肌病（ACM）是一种遗传性心肌疾病，由编码核膜蛋白跨膜蛋白 43（TMEM43）的基因中的杂合错义突变引起。该疾病的特征是肌细胞丧失和纤维脂肪替代，导致危及生命的室性心律失常和心脏性猝死。然而，TMEM43 在 ACM 发病机制中的作用仍知之甚少。在这项研究中，我们使用 Tol2 系统生成了心肌细胞特异性过表达 eGFP 连接的全长人野生型（WT）TMEM43 和两种遗传变异体（c.1073C>T，p.S358L；c.332C>T，p.P111L）的转基因斑马鱼品系。WT 和 p.P111L 突变 TMEM43 的过表达与 mTOR 通路和核糖体生物发生的转录激活有关，并导致心脏增大和心肌细胞肥大。有趣的是，突变的 p.S358L TMEM43 被发现不稳定，并在胚胎和成年心脏中部分重新分布到细胞质中。此外，两种 TMEM43 变体在幼年阶段都表现出心脏形态缺陷和心肌内超微结构变化，并伴有成年期基因表达谱的失调。最后，CRISPR/Cas9 突变体表现出年龄依赖性的心脏表型，成年时心脏增大。总之，我们的研究结果表明，在 TMEM43 相关心肌病中，超微结构重塑和转录组改变是导致结构性和功能性心脏缺陷发展的基础。
