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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondria! function
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Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondria! function

机译：患有肌病理性疾病的人类肌肉疾病的肌肉活检显示线粒体的常见改变！功能

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摘要

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases.
机译：肌肉疾病在临床和遗传上是异质的，表现为营养不良，炎症和肌病性病理等。我们先前关于成肌和炎症的心脏毒素小鼠模型的研究将肌肉病理与线粒体损伤和氧化应激联系在一起。在这项研究中，我们调查了人类肌肉疾病是否显示线粒体变化。肌肉疾病患者的肌肉活检，表现为功能障碍性疾病（dysfy）（营养不良性病理; n = 43），多发性肌炎（PM）（炎症性病理; n = 24）和远端肌病并伴有液泡（DMRV）（远端肌病; n = 31）进行了分析。通过酶组织化学（SDH和COX-SDH），电子显微镜（真空化和cr变化）和生化分析（ADP / ATP比显着增加），在dysfy，PM和DMRV病例中发现了线粒体损伤（蓝色和COX缺乏的纤维参差不齐） ）。通过等压标记对所有三种肌肉疾病的肌肉线粒体进行蛋白质组学分析，通过等压和绝对定量标记以及液相色谱-串联质谱（LC-MS / MS）分析，证明了电子转运链（ETC）复杂亚基，装配因子的下调和克雷布斯循环酶。有趣的是，三种病理中共有80种表达不足的蛋白。 ETC和克雷布斯循环酶活性的测定验证了MS数据。来自肌肉病理学的线粒体蛋白还显示出较高的色氨酸（Trp）氧化，在心脏毒素模型中也证实了这一点。分子模型预测Trp氧化会改变线粒体蛋白的局部结构。我们的数据突出了肌肉病理中的线粒体变化，表现为形态学变化，线粒体蛋白质组变化和蛋白质氧化，从而确立了线粒体损伤在人类肌肉疾病中的作用。

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