Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress
Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress
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DOI：
10.1016/s0960-8966(02)00284-5
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发表时间：
2003-05-01
影响因子：
2.8
通讯作者：
Figlewicz, DA
中科院分区：
文献类型：
--
作者：
Winokur, ST;Barrett, K;Figlewicz, DA
面肩肱型肌营养不良症是一种不寻常的遗传机制导致的常染色体显性遗传疾病。该突变是3.3 kb亚端粒重复序列的缺失，似乎破坏了4 q35基因表达的区域调节。负责面肩肱型肌营养不良症的特定基因尚未确定。然而，面肩肱型肌营养不良症成肌细胞表现出的“空泡/坏死”表型表明，异常基因表达发生在面肩肱型肌营养不良症肌肉发育的早期。为了验证这一假设，进行了面肩肱型肌营养不良症和对照成肌细胞的整体基因表达谱分析和体外表征。参与几个细胞过程，如氧化应激的基因被发现失调。体外研究证实了这种对氧化应激的敏感性，因为增殖期面肩肱型肌营养不良症成肌细胞在暴露于氧化应激物百草枯时表现出极大的活力降低。在正常或疾病对照成肌细胞中，或在分化为多核肌管的任何细胞系中均未观察到这种效应。细胞周期蛋白依赖性激酶抑制剂p21的免疫细胞化学研究表明，在面肩肱型肌营养不良成肌细胞中表达增加，提示早期细胞周期停滞。另一个区分面肩肱型肌营养不良症与对照的过程涉及细胞外基质成分的转录。面肩肱型肌营养不良成肌细胞中弹性蛋白、核心蛋白聚糖、光蛋白聚糖和细胞外基质重塑因子TIMP 3的表达减少。这些研究表明，面肩肱型肌营养不良症肌营养不良症的结果从早期肌发生的缺陷，表现为增加的敏感性氧化应激，形态畸变和早期细胞周期停滞。(C)2003 Elsevier Science B. V.保留所有权利。
Facioscapulohumeral muscular dystrophy is an autosomal dominant disorder resulting from an unusual genetic mechanism. The mutation, a deletion of 3.3 kb subtelomeric repeats, appears to disrupt the regional regulation of 4q35 gene expression. The specific gene(s) responsible for facioscapulohumeral muscular dystrophy have not been identified. However, the 'vacuolar/necrotic' phenotype exhibited by facioscapulohumeral muscular dystrophy myoblasts suggests that aberrant gene expression occurs early in facioscapulohumeral muscular dystrophy muscle development. In order to test this hypothesis, global gene expression profiling and in vitro characterization of facioscapulohumeral muscular dystrophy and control myoblasts were carried out. Genes involved in several cellular processes such as oxidative stress were found to be dysregulated. In vitro studies confirmed this susceptibility to oxidative stress, as proliferative stage facioscapulohumeral muscular dystrophy myoblasts exhibit greatly reduced viability when exposed to the oxidative stressor paraquat. This effect was not seen in either normal or disease control myoblasts, or in any of the cell lines upon differentiation to multinucleated myotubes. lmmunocytochemical studies of the cyclin dependent kinase inhibitor p21 demonstrated increased expression in facioscapulohumeral muscular dystrophy myoblasts, suggesting an early cell cycle arrest. Another process distinguishing facioscapulohumeral muscular dystrophy from controls involves the transcription of extracellular matrix components. Expression of elastin, decorin, lumican and the extracellular matrix remodeling factor TIMP3 were reduced in facioscapulohumeral muscular dystrophy myoblasts. These studies suggest that facioscapulohumeral muscular dystrophy muscular dystrophy results from a defect in early myogenesis, manifested as increased susceptibility to oxidative stress, morphological aberrations and early cell cycle arrest. (C) 2003 Elsevier Science B.V. All rights reserved.