Reversible molecular pathology of skeletal muscle in spinal muscular atrophy
Reversible molecular pathology of skeletal muscle in spinal muscular atrophy
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DOI：
10.1093/hmg/ddr360
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发表时间：
2011-11-15
影响因子：
3.5
通讯作者：
Gillingwater, Thomas H.
中科院分区：
文献类型：
--
作者：
Mutsaers, Chantal A.;Wishart, Thomas M.;Gillingwater, Thomas H.
运动神经元全长存活蛋白(SMN)水平低导致运动神经元疾病--脊髓性肌萎缩症(SMA)。尽管运动神经元无疑直接参与了SMA的发病，但肌肉的作用还不是很清楚。我们发现，在出现症状前的严重SMA小鼠中，骨骼肌的分子组成发生了显著的破坏，在下运动神经元中没有任何可检测到的退行性变化，并且具有与失神经肌肉不同的分子图谱。蛋白质组数据的功能聚类分析和DNA损伤的磷酸组蛋白H_2AX标记显示，SMA肌肉中细胞死亡途径的活性增加。在较轻的SMA小鼠模型和人类患者的肌肉活检中，在重度SMA小鼠中，电压依赖性阴离子选择通道蛋白2(Vdac2)的强劲上调和小白蛋白的下调得到证实。使用FDA批准的组蛋白去乙酰化酶抑制剂Suberoylanilde异羟肟酸治疗的小鼠骨骼肌的分子病理学得到了改善。我们的结论是，骨骼肌的内在病理是SMA中一个重要且可逆的事件，也提示肌肉蛋白有可能作为SMA中的新的生物标志物。
Low levels of full-length survival motor neuron (SMN) protein cause the motor neuron disease, spinal muscular atrophy (SMA). Although motor neurons undoubtedly contribute directly to SMA pathogenesis, the role of muscle is less clear. We demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic severe SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomic data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. Robust upregulation of voltage-dependent anion-selective channel protein 2 (Vdac2) and downregulation of parvalbumin in severe SMA mice was confirmed in a milder SMA mouse model and in human patient muscle biopsies. Molecular pathology of skeletal muscle was ameliorated in mice treated with the FDA-approved histone deacetylase inhibitor, suberoylanilide hydroxamic acid. We conclude that intrinsic pathology of skeletal muscle is an important and reversible event in SMA and also suggest that muscle proteins have the potential to act as novel biomarkers in SMA.