Biomechanical characterization of a desminopathy in primary human myoblasts
Biomechanical characterization of a desminopathy in primary human myoblasts
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DOI：
10.1016/j.bbrc.2012.02.083
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发表时间：
2012-03-23
影响因子：
3.1
通讯作者：
Fabry, Ben
中科院分区：
文献类型：
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作者：
Bonakdar, Navid;Luczak, Justyna;Fabry, Ben
染色体2q35上人类结蛋白基因的杂合突变会导致遗传性和散发性肌病以及心肌病。突变结蛋白的表达导致了肌节外结蛋白细胞骨架的部分破坏和肌浆内蛋白的异常聚集。从结蛋白基因缺陷到进行性肌肉损伤的确切分子途径和顺序步骤仍不清楚。我们测试了突变的结蛋白是否改变了原代培养的成肌细胞的生物力学特性和内在机械应力反应，这些细胞来自一名携带R350P结蛋白杂合突变的患者。与野生型对照相比，未分化的突变结蛋白成肌细胞表现出细胞死亡和底物分离的增加，这是对柔性膜上循环拉伸的反应。此外，使用纤维连接蛋白包裹的珠子对成肌细胞进行磁钳显微流变仪测量显示，病变细胞的硬度增加。我们的发现提供了第一个证据，改变的机械性能可能有助于进行性横纹肌病理在牙周病。我们推测，突变结蛋白的表达导致机械硬度增加，从而导致对应变的过度机械应力，从而增加机械易损性和肌肉细胞的损伤。(C)2012 Elsevier Inc.保留所有权利。
Heterozygous mutations of the human desmin gene on chromosome 2q35 cause hereditary and sporadic myopathies and cardiomyopathies. The expression of mutant desmin brings about partial disruption of the extra sarcomeric desmin cytoskeleton and abnormal protein aggregation in the sarcoplasm of striated muscle cells. The precise molecular pathways and sequential steps that lead from a desmin gene defect to progressive muscle damage are still unclear. We tested whether mutant desmin changes the biomechanical properties and the intrinsic mechanical stress response of primary cultured myoblasts derived from a patient carrying a heterozygous R350P desmin mutation. Compared to wildtype controls, undifferentiated mutant desmin myoblasts revealed increased cell death and substrate detachment in response to cyclic stretch on flexible membranes. Moreover, magnetic tweezer microrheometry of myoblasts using fibronectin-coated beads showed increased stiffness of diseased cells. Our findings provide the first evidence that altered mechanical properties may contribute to the progressive striated muscle pathology in desminopathies. We postulate that the expression of mutant desmin leads to increased mechanical stiffness, which results in excessive mechanical stress in response to strain and consecutively to increased mechanical vulnerability and damage of muscle cells. (C) 2012 Elsevier Inc. All rights reserved.