Lem2 is essential for cardiac development by maintaining nuclear integrity.
Lem2 is essential for cardiac development by maintaining nuclear integrity.
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DOI：
10.1093/cvr/cvad061
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发表时间：
2023-09-05
影响因子：
10.8
通讯作者：
中科院分区：
文献类型：
--
作者：
核膜完整性对于细胞核和细胞质的区隔是必不可少的。重要的是，编码核包膜（NE）和相关蛋白的基因突变是家族性扩张性心肌病的第二大原因。其中一种引起人类心肌病并影响小鼠心脏发育的NE蛋白是Lem2。然而，它在心脏中的作用仍然知之甚少。我们在胚胎心肌细胞（Lem2 cKO）或成年心肌细胞（Lem2 iCKO）中特异性切除Lem2，并进行了详细的生理、组织和细胞分析。使用高分辨率显微镜进行三维重建和详细的形态学分析。rna测序和免疫荧光鉴定了改变的途径和细胞表型，并分离心肌细胞以更详细地询问核完整性。此外，超声心动图提供了Lem2 iCKO成年小鼠的生理评估。我们发现Lem2对心脏发育至关重要，而Lem2 cKO小鼠的心脏在形态和转录上都不发达。le2 cKO心脏显示出高水平的DNA损伤、核破裂和细胞凋亡。至关重要的是，我们发现这些缺陷是由肌肉收缩驱动的，因为它们可以通过抑制肌球蛋白收缩和l型钙通道来改善。相反，将成人心肌细胞中的Lem2水平降低至45%不会导致18个月大的明显心功能障碍。我们的数据表明，Lem2对胎儿心脏新生NE的完整性至关重要，并保护细胞核免受肌肉收缩的机械力的影响。相比之下，成人心脏不受部分Lem2消耗的明显影响，这可能是由于更成熟的NE和对机械应力的适应增加。综上所述，这些数据提供了对Lem2突变和一般心层病患者心肌病的潜在机制的见解。
Nuclear envelope integrity is essential for the compartmentalization of the nucleus and cytoplasm. Importantly, mutations in genes encoding nuclear envelope (NE) and associated proteins are the second highest cause of familial dilated cardiomyopathy. One such NE protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in the heart remains poorly understood. We generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or in adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue, and cellular analyses. High-resolution episcopic microscopy was used for three-dimensional reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided a physiological assessment of Lem2 iCKO adult mice. We found that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and L-type calcium channels. Conversely, reducing Lem2 levels to ∼45% in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age. Our data suggest that Lem2 is critical for integrity at the nascent NE in foetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. In contrast, the adult heart is not detectably affected by partial Lem2 depletion, perhaps owing to a more established NE and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general.
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