Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells
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DOI：
10.1038/s41563-019-0563-5
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发表时间：
2020-04-01
期刊：
影响因子：
41.2
通讯作者：
Lammerding, Jan
中科院分区：
文献类型：
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作者：
Earle, Ashley J.;Kirby, Tyler J.;Lammerding, Jan
导致肌营养不良症的核纤层蛋白突变显示降低核膜稳定性，导致机械诱导的核膜破裂、DNA损伤和导致肌细胞死亡的DNA损伤反应途径的激活。LMNA基因编码核被膜（NE）蛋白核纤层蛋白A/C，LMNA基因突变可导致Emery-Dreifuss肌营养不良症、先天性肌营养不良症和其他统称为核纤层蛋白病的疾病。这些疾病的发病机制仍不完全清楚。使用三种肌肉层粘连蛋白病的小鼠模型和来自LMNA相关肌营养不良症个体的肌肉活检，我们发现Lmna突变降低了核稳定性并导致骨骼肌细胞中NE的短暂破裂，导致DNA损伤，DNA损伤反应激活和细胞活力降低。在小鼠模型中，NE和DNA损伤由骨骼肌成熟过程中的核迁移引起，并与疾病的严重程度相关。肌细胞核上的细胞骨架力的减少防止NE损伤，并在Lmna突变体肌纤维中挽救肌纤维功能和活力，表明肌纤维功能障碍是机械诱导的NE损伤的结果。总之，这些发现暗示机械诱导的DNA损伤是LMNA骨骼肌疾病的致病因素。
Lamin mutations responsible for muscular dystrophy are shown to reduce nuclear envelope stability, resulting in mechanically induced nuclear envelope rupture, DNA damage and activation of DNA damage response pathways that lead to muscle cell death. Preventing nuclear envelope damage by reducing cytoskeletal forces on the nucleus improves muscle fibre health and function.Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A/C, cause Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy and other diseases collectively known as laminopathies. The mechanisms responsible for these diseases remain incompletely understood. Using three mouse models of muscle laminopathies and muscle biopsies from individuals with LMNA-related muscular dystrophy, we found that Lmna mutations reduced nuclear stability and caused transient rupture of the NE in skeletal muscle cells, resulting in DNA damage, DNA damage response activation and reduced cell viability. NE and DNA damage resulted from nuclear migration during skeletal muscle maturation and correlated with disease severity in the mouse models. Reduction of cytoskeletal forces on the myonuclei prevented NE damage and rescued myofibre function and viability in Lmna mutant myofibres, indicating that myofibre dysfunction is the result of mechanically induced NE damage. Taken together, these findings implicate mechanically induced DNA damage as a pathogenic contributor to LMNA skeletal muscle diseases.