The time course of the adaptations of human muscle proteome to bed rest and the underlying mechanisms
The time course of the adaptations of human muscle proteome to bed rest and the underlying mechanisms
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DOI：
10.1113/jphysiol.2012.240267
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发表时间：
2012-10-01
影响因子：
5.5
通讯作者：
Pellegrino, Maria Antonietta
中科院分区：
文献类型：
--
作者：
Brocca, Lorenza;Cannavino, Jessica;Pellegrino, Maria Antonietta
活性氧的产生和去除之间的不平衡是否是人类四肢肌肉废用性骨骼肌萎缩的主要触发因素以及其潜在机制仍然存在争议。在人类废用卧床模型中，氧化还原失衡、抗氧化防御系统受损和代谢紊乱很早就发生，在股外侧肌萎缩发生之前，并持续卧床 35 天。 PGC-1a（肌肉代谢的主控制器）的下调和 SREBP-1（脂质合成的主控制器）的上调可能通过线粒体功能障碍引发废用适应，而 AMP 激酶（一种能量传感器途径）则没有改变。目前和之前对同一受试者的结果表明，肌肉萎缩、骨骼肌代谢受损、全身氧化代谢受损、胰岛素敏感性和中度炎症之间存在因果关系，而这些是缺乏运动相关疾病的主要危险因素。摘要 为了全面了解人类骨骼肌废用的复杂适应过程并进一步了解其潜在机制，我们参加了两次卧床休息活动，一次持续 35 天，另一次持续 24 天。在第一次卧床休息 (BR) 活动中，通过对 9 名受试者的股外侧肌样本进行蛋白质组学分析，发现肌原纤维蛋白、代谢酶和抗氧化防御系统在 BR 8 天和 35 天后均下调。这种深刻的改变发生在废用性萎缩发生之前的早期（BR 8 天后），并在 BR 期间持续存在（BR 35 天后）。为了了解观察到的蛋白质适应的机制，使用第二次卧床休息运动（九名受试者）的肌肉活检来评估肌肉蛋白质分解和肌肉蛋白质合成（MuRF-1和atrogin-1；Akt和p70S6K）、自噬（Beclin-1、p62、LC3、bnip3、 组织蛋白酶-L)、抗氧化防御系统 (NRF2) 和能量代谢 (PGC-1a、SREBP-1、AMPK) 的表达。结果表明：（i）氧化还原失衡和肌肉蛋白质组重塑发生较早，并通过 BR 持续存在； (ii) 能量代谢受损是一种早期且持续的现象，包括氧化代谢和糖酵解代谢； (iii) 尽管泛素蛋白酶体和自噬这两个主要分解代谢系统都可能导致 BR 后期萎缩的进展，但不能排除蛋白质合成减少的可能性； (iv) PGC-1a 减少，同时 SREBP-1 上调，可能是代谢损伤的触发因素，而 AMPK 途径未改变。
Key points It is still debated whether an imbalance between production and removal of reactive oxygen species is a major trigger of disuse skeletal muscle atrophy in human limb muscles and what the underlying mechanisms are. In the bed rest model of human disuse, redox imbalance, impairment of antioxidant defence systems and metabolic derangement occurred early, before vastus lateralis muscle atrophy developed, and persisted through 35 days of bed rest. Down-regulation of PGC-1a, a master controller of muscle metabolism, and up-regulation of SREBP-1, a master controller of lipid synthesis, are likely to have triggered disuse adaptations through mitochondrial dysfunction, whereas AMP kinase, an energy sensor pathway, was unaltered. The present and previous results on the same subjects suggest a causal link between muscle atrophy, impaired skeletal muscle metabolism, impaired whole body oxidative metabolism, and insulin sensitivity and moderate inflammation, which are major risk factors of physical inactivity related diseases. Abstract In order to get a comprehensive picture of the complex adaptations of human skeletal muscle to disuse and further the understanding of the underlying mechanisms, we participated in two bed rest campaigns, one lasting 35 days and one 24 days. In the first bed rest (BR) campaign, myofibrillar proteins, metabolic enzymes and antioxidant defence systems were found to be down-regulated both post-8 days and post-35 days BR by proteomic analysis of vastus lateralis muscle samples from nine subjects. Such profound alterations occurred early (post-8 days BR), before disuse atrophy developed, and persisted through BR (post-35 days BR). To understand the mechanisms underlying the protein adaptations observed, muscle biopsies from the second bed rest campaign (nine subjects) were used to evaluate the adaptations of master controllers of the balance between muscle protein breakdown and muscle protein synthesis (MuRF-1 and atrogin-1; Akt and p70S6K), of autophagy (Beclin-1, p62, LC3, bnip3, cathepsin-L), of expression of antioxidant defence systems (NRF2) and of energy metabolism (PGC-1a, SREBP-1, AMPK). The results indicate that: (i) redox imbalance and remodelling of muscle proteome occur early and persist through BR; (ii) impaired energy metabolism is an early and persistent phenomenon comprising both the oxidative and glycolytic one; (iii) although both major catabolic systems, ubiquitin proteasome and autophagy, could contribute to the progression of atrophy late into BR, a decreased protein synthesis cannot be ruled out; (iv) a decreased PGC-1a, with the concurrence of SREBP-1 up-regulation, is a likely trigger of metabolic impairment, whereas the AMPK pathway is unaltered.