Muscle wasting in patients with end-stage renal disease or early-stage lung cancer: common mechanisms at work
Muscle wasting in patients with end-stage renal disease or early-stage lung cancer: common mechanisms at work
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DOI：
10.1002/jcsm.12376
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发表时间：
2019-04-01
影响因子：
8.9
通讯作者：
Taillandier, Daniel
中科院分区：
文献类型：
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作者：
Aniort, Julien;Stella, Alexandre;Taillandier, Daniel
背景肌肉质量的丧失导致许多疾病，如癌症和肾衰竭，导致虚弱综合征，并与死亡风险增加有关。在动物模型上进行的研究已经揭示了肌肉蛋白水解的优势作用，特别是泛素蛋白酶体系统（UPS）的激活。在人类中进行的研究仍然很少，特别是在肾功能不全的情况下。一个共同的萎缩程序是否独立于疾病的性质而存在，仍有待确定。这项工作的目的是确定癌症和肾衰竭患者萎缩骨骼肌中转录组水平或蛋白质组水平的常见修饰。方法在早期介入治疗中进行肌肉活检（未治疗且未检测到肌肉损失）肺癌（LC）、长期血液透析（HD）或健康（CT）患者（每组n = 7; 86%男性; CT、LC和HD组分别为69.6 +/- 11.4、67.9 +/- 8.6和70.2 +/- 7.9岁，P > 0.9）。通过定量实时PCR测量UPS、自噬和凋亡系统的成员的基因表达。通过鸟枪蛋白质组学对可溶性肌肉蛋白质组进行了全面分析，以研究改变的过程。结果在LC和HD患者中，几种UPS和自噬相关酶的表达均增加。E3连接酶MuRF 1（+56至78%，P < 0.01），MAFbx（+68至84%，P = 0.02），Hdm 2（+37至59%，P = 0.02），和MUSA 1/Fbxo 30自噬相关基因CTPL（+33至47%，P = 0.03）和SQSTM 1（+47至137%，P < 0.01）表达增强。质谱鉴定了>1700种蛋白质，主成分分析揭示了与三组患者相匹配的三种差异蛋白质组。正交偏最小二乘判别分析建立了一个模型，区分的肌肉病变患者（LC或HD）的CT科目。选择对模型贡献最大的蛋白质。功能分析显示多达238种蛋白质属于9个代谢过程（炎症反应，蛋白水解，细胞骨架组织，葡萄糖代谢，肌肉收缩，氧化剂解毒，能量代谢，脂肪酸代谢和细胞外基质）参与和/或改变萎缩的LC和HD患者的程序。这通过共表达网络分析得到证实。结论：我们能够在不同病因（早期LC与长期肾衰竭）的患者中识别出高度相似的几种代谢途径的修饰。这有力地表明，一个共同的萎缩程序独立于疾病存在于人类。
Background Loss of muscle mass worsens many diseases such as cancer and renal failure, contributes to the frailty syndrome, and is associated with an increased risk of death. Studies conducted on animal models have revealed the preponderant role of muscle proteolysis and in particular the activation of the ubiquitin proteasome system (UPS). Studies conducted in humans remain scarce, especially within renal deficiency. Whether a shared atrophying programme exists independently of the nature of the disease remains to be established. The aim of this work was to identify common modifications at the transcriptomic level or the proteomic level in atrophying skeletal muscles from cancer and renal failure patients. Methods Muscle biopsies were performed during scheduled interventions in early-stage (no treatment and no detectable muscle loss) lung cancer (LC), chronic haemodialysis (HD), or healthy (CT) patients (n = 7 per group; 86% male; 69.6 +/- 11.4, 67.9 +/- 8.6, and 70.2 +/- 7.9 years P > 0.9 for the CT, LC, and HD groups, respectively). Gene expression of members of the UPS, autophagy, and apoptotic systems was measured by quantitative real-time PCR. A global analysis of the soluble muscle proteome was conducted by shotgun proteomics for investigating the processes altered. Results We found an increased expression of several UPS and autophagy-related enzymes in both LC and HD patients. The E3 ligases MuRF1 (+56 to 78%, P < 0.01), MAFbx (+68 to 84%, P = 0.02), Hdm2 (+37 to 59%, P = 0.02), and MUSA1/Fbxo30 (+47 to 106%, P = 0.01) and the autophagy-related genes CTPL (+33 to 47%, P = 0.03) and SQSTM1 (+47 to 137%, P < 0.01) were overexpressed. Mass spectrometry identified >1700 proteins, and principal component analysis revealed three differential proteomes that matched to the three groups of patients. Orthogonal partial least square discriminant analysis created a model, which distinguished the muscles of diseased patients (LC or HD) from those of CT subjects. Proteins that most contributed to the model were selected. Functional analysis revealed up to 238 proteins belonging to nine metabolic processes (inflammatory response, proteolysis, cytoskeleton organization, glucose metabolism, muscle contraction, oxidant detoxification, energy metabolism, fatty acid metabolism, and extracellular matrix) involved in and/or altered by the atrophying programme in both LC and HD patients. This was confirmed by a co-expression network analysis. Conclusions We were able to identify highly similar modifications of several metabolic pathways in patients exhibiting diseases with different aetiologies (early-stage LC vs. long-term renal failure). This strongly suggests that a common atrophying programme exists independently of the disease in human.