Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes
Parallel protein and transcript profiles of FSHD patient muscles correlate to the D4Z4 arrangement and reveal a common impairment of slow to fast fibre differentiation and a general deregulation of MyoD-dependent genes
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DOI：
10.1002/pmic.200600056
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发表时间：
2006-10-01
期刊：
影响因子：
3.4
通讯作者：
Gelfi, Cecilia
中科院分区：
文献类型：
--
作者：
Celegato, Barbara;Capitanio, Daniele;Gelfi, Cecilia
在这里，我们提出了人类神经肌肉疾病在转录和蛋白质组水平的第一个研究。常染色体显性面肩肱肌营养不良症（FSHD）是由4-q35基因座端粒区D4 Z4内整数个3.3 kb Kpn I重复序列缺失引起的。我们结合肌肉特异性cDNA微阵列平台与蛋白质组学研究，分析携带可变数量Kpn I重复序列的患者的肌肉活检。无监督聚类分析根据Kpn I重复数将患者分为三类。表达数据揭示了FSHD肌肉中从快速糖酵解到缓慢氧化表型的转变，这伴随着参与响应氧化应激的蛋白质的缺陷。此外，FSHD个体在MyoD依赖的基因网络中显示出破坏，这表明在肌发生过程中在转录水平上存在共调节。我们还讨论了D4 Z4收缩可能影响一组参与肌发生的基因的表达以及成体组织中卫星细胞再生途径的假设。肌肉萎缩可能是由于卫星细胞无法成功分化成成熟纤维，以及纤维中氧化代谢增加引起的活性氧（ROS）失衡引起的结构损伤累积所致。
Here, we present the first study of a human neuromuscular disorder at transcriptional and proteomic level. Autosomal dominant facio-scapulo-humeral muscular dystrophy (FSHD) is caused by a deletion of an integral number of 3.3-kb KpnI repeats inside the telomeric region D4Z4 at the 4-q35 locus. We combined a muscle-specific cDNA microarray platform with a proteomic investigation to analyse muscle biopsies of patients carrying a variable number of KpnI repeats. Unsupervised cluster analysis divides patients into three classes, according to their KpnI repeat number. Expression data reveal a transition from fast-glycolytic to slow-oxidative phenotype in FSHD muscle, which is accompanied by a deficit of proteins involved in response to oxidative stress. Besides, FSHD individuals show a disruption in the MyoD-dependent gene network suggesting a coregulation at transcriptional level during myogenesis. We also discuss the hypothesis that D4Z4 contraction may affect in trans the expression of a set of genes involved in myogenesis, as well as in the regeneration pathway of satellite cells in adult tissue. Muscular wasting could result from the inability of satellite cells to successfully differentiate into mature fibres and from the accumulation of structural damages caused by a reactive oxygen species (ROS) imbalance induced by an increased oxidative metabolism in fibres.