Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

中文翻译：

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中间丝和微管之间的平衡保持了心肌细胞的核结构。

原理：机械力通过核骨架和细胞骨架（LINC）复合物的连接子传导至核反应，该复合物将细胞骨架与核层和相关的染色质偶联。虽然LINC复合物的破坏会引起心肌病，但在心肌细胞中，人们对桥接核骨架与细胞骨架的相关相互作用知之甚少，在心肌细胞中，细胞骨架的组织是独特的。此外，尽管微管和结蛋白中间丝与心肌细胞核紧密结合，但这些相互作用的重要性尚不清楚。目的：在这里，我们试图确定与LINC复合物的细胞骨架相互作用如何调节心肌细胞的核稳态。方法和结果：为此，我们急性破坏了LINC复合物，微管，肌动蛋白，和中间丝，并通过超分辨率成像，生物物理和基因组方法相结合，评估了对大鼠心室心肌细胞核形态和基因组组织的影响。我们发现，需要动态微管和结蛋白中间丝之间的平衡，以保持核的形状以及核被膜和椎板的保真度。去除结蛋白（或LINC络合物中的结合伴侣-Nesprin [核包膜蛋白重复蛋白] -3）后，聚合的微管会使细胞核塌陷并驱动核膜的折叠。这导致DNA损伤，基因组组织丢失和广泛的转录变化。核完整性的崩溃伴随着收缩功能的损害，并且可能导致与结蛋白相关的肌病中观察到的病理生理变化。结论：破坏结蛋白与细胞核的束缚会导致核稳态的丧失和心肌细胞功能的快速改变。我们的数据表明，需要由中间细丝和微管施加的力平衡才能维持心肌细胞的核结构和基因组组织。