Altered nuclear dynamics in MDX myofibers
Altered nuclear dynamics in MDX myofibers
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DOI：
10.1152/japplphysiol.00857.2016
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发表时间：
2017-03-01
影响因子：
3.3
通讯作者：
Lovering, Richard M.
中科院分区：
文献类型：
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作者：
Iyer, Shama R.;Shah, Sameer B.;Lovering, Richard M.
杜氏肌营养不良症（DMD）是一种遗传性疾病，其中肌营养不良蛋白的缺乏导致进行性肌肉变性和虚弱。虽然遗传基础是已知的，但营养不良性骨骼肌的病理生理学仍不清楚。我们研究了DMD（MDX）（肌营养不良蛋白缺失）小鼠肌纤维在野生型（WT）和肌营养不良小鼠模型中的核运动。我们还研究了核骨架和细胞骨架（LINC）复合物的连接蛋白的表达，以及通过组蛋白H3乙酰化和多聚腺苷酸结合核蛋白-1的核转录活性。由于细胞核的运动不仅依赖于LINC，而且依赖于微管，因此我们分析了WT和MDX肌纤维中的微管密度和组织，包括应用独特的3D工具来评估微管核心结构。MDX肌纤维中的细胞核在运动距离和速度方面都比WT肌纤维中的细胞核更移动的。MDX肌肉显示nesprin-1的表达和标记强度降低，nesprin-1是一种将细胞核连接到微管和肌动蛋白细胞骨架的LINC蛋白。MDX细胞核也表现出改变的转录活性。以前的研究确定，在皮层微管结构被破坏的MDX肌纤维;我们的分析扩展这些发现，显示微管结构的核心也被破坏。此外，我们研究了畸形的MDX肌纤维，以更好地理解肌纤维形态学改变与微管结构在营养不良肌肉中观察到的潜在损伤易感性中的作用。我们将形态学和微管结构的概念，简化的有限元数学模型的肌纤维力学，这表明更大的贡献，肌纤维形态比微管结构的肌肉生物力学性能。微管提供了核运动的手段，但在肌营养不良小鼠模型（MDX）（肌营养不良蛋白无效）肌肉中显示出改变的组织。在这里，MDX肌纤维显示增加核运动，改变转录活性，并改变核骨架和细胞骨架复合体表达的连接。微管结构被纳入被动拉伸的有限元建模，揭示了纤维畸形的作用，通常发现在MDX肌肉。结果表明，在MDX肌肉微管结构的改变影响核运动，这是必不可少的肌肉功能。
Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to progressive muscle degeneration and weakness. Although the genetic basis is known, the pathophysiology of dystrophic skeletal muscle remains unclear. We examined nuclear movement in wild-type (WT) and muscular dystrophy mouse model for DMD (MDX) (dystrophin-null) mouse myofibers. We also examined expression of proteins in the linkers of nucleoskeleton and cytoskeleton (LINC) complex, as well as nuclear transcriptional activity via histone H3 acetylation and polyadenylatebinding nuclear protein-1. Because movement of nuclei is not only LINC dependent but also microtubule dependent, we analyzed microtubule density and organization in WT and MDX myofibers, including the application of a unique 3D tool to assess microtubule core structure. Nuclei in MDX myofibers were more mobile than in WT myofibers for both distance traveled and velocity. MDX muscle shows reduced expression and labeling intensity of nesprin-1, a LINC protein that attaches the nucleus to the microtubule and actin cytoskeleton. MDX nuclei also showed altered transcriptional activity. Previous studies established that microtubule structure at the cortex is disrupted in MDX myofibers; our analyses extend these findings by showing that microtubule structure in the core is also disrupted. In addition, we studied malformed MDX myofibers to better understand the role of altered myofiber morphology vs. microtubule architecture in the underlying susceptibility to injury seen in dystrophic muscles. We incorporated morphological and microtubule architectural concepts into a simplified finite element mathematical model of myofiber mechanics, which suggests a greater contribution of myofiber morphology than microtubule structure to muscle biomechanical performance. NEW & NOTEWORTHY Microtubules provide the means for nuclear movement but show altered organization in the muscular dystrophy mouse model (MDX) (dystrophin-null) muscle. Here, MDX myofibers show increased nuclear movement, altered transcriptional activity, and altered linkers of nucleoskeleton and cytoskeleton complex expression compared with healthy myofibers. Microtubule architecture was incorporated in finite element modeling of passive stretch, revealing a role of fiber malformation, commonly found in MDX muscle. The results suggest that alterations in microtubule architecture in MDX muscle affect nuclear movement, which is essential for muscle function.