Novel events in the molecular regulation of muscle mass in critically ill patients
Novel events in the molecular regulation of muscle mass in critically ill patients
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DOI：
10.1113/jphysiol.2011.206193
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发表时间：
2011-08-01
影响因子：
5.5
通讯作者：
Greenhaff, Paul L.
中科院分区：
文献类型：
--
作者：
Constantin, Despina;McCullough, Justine;Greenhaff, Paul L.
重症患者会出现明显的骨骼肌萎缩，但导致这种萎缩的分子机制在很大程度上尚未得到解决。因此，我们研究了从10例患者和10例年龄和性别匹配的健康对照中获得的股外侧肌活检样本中的关键基因和蛋白质，这些基因和蛋白质是从细胞和动物研究中确定的，以控制蛋白质的合成和分解。肌肉细胞因子IL-6和TNF-α mRNA在患者中高于对照组（6.5倍; P < 0.001和2倍; P < 0.01）。从肌肉蛋白质分解的角度来看，肌肉特异性E3连接酶（MAFbx和MuRF 1）在mRNA（4.5倍; P < 0.05和2.5倍; P < 0.05）和蛋白质（5倍; P < 0.001和4.5倍; P < 0.001）水平上在患者中更高。20 S蛋白酶体mRNA和蛋白表达在胃癌组均高于正常对照组（5倍; P < 0.001和2.5倍; P < 0.01）。组织蛋白酶-LmRNA水平升高2倍（P < 0.01），钙蛋白酶-3 mRNA水平降低2倍（P < 0.01），蛋白水平降低4倍（P < 0.01）。另一个新的观察结果是患者中肌生长抑制素mRNA和蛋白的表达分别增加了3倍（P < 0.05）和8.5倍（P < 0.001）。在患者中观察到调节翻译起始因子激活和蛋白质合成的蛋白质（Akt 1、GSK 3 α、β、mTOR、p70 S6 K和4 E-BP 1）广泛去磷酸化（失活），这是由其mRNA的增加引起的。最后，PDK 4 mRNA和蛋白在患者中分别高2倍（P < 0.05）和2.6倍（P < 0.01）。总之，我们显示了分子事件的全面改变，这些分子事件被认为减少了危重患者的肌肉质量和碳水化合物（CHO）氧化。然而，这些分解代谢事件与转录水平上的合成代谢恢复的细胞程序相匹配。这表明患者肌肉中的高分子可塑性，并且保持肌肉质量和代谢功能的策略应集中于维持Akt磷酸化和抑制肌生长抑制素表达。
Critically ill patients experience marked skeletal muscle atrophy, but the molecular mechanisms responsible for this are largely unresolved. Therefore, we investigated key genes and proteins, identified from cell and animal studies to control protein synthesis and breakdown, in vastus lateralis biopsy samples obtained from 10 patients and 10 age-and sex-matched healthy controls. Muscle cytokines IL-6 and TNF-alpha mRNA were higher in patients than in controls (6.5-fold; P < 0.001 and 2-fold; P < 0.01). From the perspective of muscle protein breakdown, muscle-specific E3-ligases (MAFbx and MuRF1) were higher in patients at mRNA (4.5-fold; P < 0.05 and 2.5-fold; P < 0.05) and protein (5-fold; P < 0.001 and 4.5-fold; P < 0.001) level. Furthermore, 20S proteasome mRNA and protein were higher in patients (5-fold; P < 0.001 and 2.5-fold; P < 0.01). Cathepsin-L mRNA was 2-fold higher (P < 0.01), whilst calpain-3 mRNA (2-fold; P < 0.01) and protein (4-fold; P < 0.01) were lower inpatients. Another novel observation was the 3-fold (P < 0.05) and 8.5-fold (P < 0.001) higher expression of myostatin mRNA and protein in patients. Widespread dephosphorylation (inactivation) of proteins regulating translation initiation factor activation and protein synthesis (Akt1, GSK3 alpha, beta, mTOR, p70S6K and 4E-BP1) was observed in patients, which was paralleled by increases in their mRNAs. Finally, PDK4 mRNA and protein was 2-fold (P < 0.05) and 2.6-fold (P < 0.01), respectively, higher in patients. In conclusion, we showed comprehensive alterations in molecular events thought to reduce muscle mass and carbohydrate (CHO) oxidation in critically ill patients. Nevertheless, these catabolic events were matched by a cellular programme of anabolic restoration at the transcriptional level. This shows a high molecular plasticity in the muscle of patients, and strategies to preserve muscle mass and metabolic function should focus on maintaining Akt phosphorylation and inhibiting myostatin expression.