Pavlov Daria Amiad, Heffler Julie, Suay-Corredera Carmen, Dehghany Mohammad, Shen Kaitlyn M, Zuela-Sopilniak Noam, Randell Rani, Uchida Keita, Jain Rajan, Shenoy Vivek, Lammerding Jan, Prosser Benjamin
Department of Physiology, Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania.
Weill Institute for Cell and Molecular Biology & Meinig School of Biomedical Engineering, Cornell University.
bioRxiv. 2024 Oct 5:2024.02.10.579774. doi: 10.1101/2024.02.10.579774.
Nuclear homeostasis requires a balance of forces between the cytoskeleton and nucleus. Mutations in the gene, which encodes the nuclear envelope proteins lamin A/C, disrupt this balance by weakening the nuclear lamina. This results in nuclear damage in contractile tissues and ultimately muscle disease. Intriguingly, disrupting the LINC complex that connects the cytoskeleton to the nucleus has emerged as a promising strategy to ameliorate associated cardiomyopathy. Yet how LINC complex disruption protects the cardiomyocyte nucleus remains unclear. To address this, we developed an assay to quantify the coupling of cardiomyocyte contraction to nuclear deformation and interrogated its dependence on the nuclear lamina and LINC complex. We found that, surprisingly, the LINC complex was mostly dispensable for transferring contractile strain to the nucleus, and that increased nuclear strain in lamin A/Cdeficient cardiomyocytes was not rescued by LINC complex disruption. Instead, LINC complex disruption eliminated the cage of microtubules encircling the nucleus. Disrupting microtubules was sufficient to prevent nuclear damage and rescue cardiac function induced by lamin A/C deficiency. We computationally simulated the stress fields surrounding cardiomyocyte nuclei and show how microtubule forces generate local vulnerabilities that damage lamin A/C-deficient nuclei. Our work pinpoints localized, microtubule-dependent force transmission through the LINC complex as a pathological driver and therapeutic target for cardiomyopathy.
核稳态需要细胞骨架和细胞核之间的力平衡。编码核膜蛋白核纤层蛋白A/C的基因突变会削弱核纤层，从而破坏这种平衡。这会导致收缩组织中的核损伤，并最终引发肌肉疾病。有趣的是，破坏连接细胞骨架和细胞核的LINC复合物已成为改善相关心肌病的一种有前景的策略。然而，LINC复合物破坏如何保护心肌细胞核仍不清楚。为了解决这个问题，我们开发了一种测定方法来量化心肌细胞收缩与核变形的耦合，并研究其对核纤层和LINC复合物的依赖性。我们发现，令人惊讶的是，LINC复合物在将收缩应变传递到细胞核方面大多是可有可无的，并且LINC复合物破坏并不能挽救核纤层蛋白A/C缺陷型心肌细胞中增加的核应变。相反，LINC复合物破坏消除了围绕细胞核的微管笼。破坏微管足以防止核损伤并挽救由核纤层蛋白A/C缺陷引起的心脏功能。我们通过计算模拟了心肌细胞核周围的应力场，并展示了微管力如何产生损害核纤层蛋白A/C缺陷型细胞核的局部脆弱性。我们的工作指出通过LINC复合物的局部、微管依赖性力传递是心肌病的病理驱动因素和治疗靶点。
