Crossland Hannah, Constantin-Teodosiu Dumitru, Gardiner Sheila M, Greenhaff Paul L
MRC/Arthritis Research UK, Centre for Musculoskeletal Ageing Research, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, U.K.
Clin Sci (Lond). 2017 Jun 22;131(13):1437-1447. doi: 10.1042/CS20170958. Print 2017 Jul 1.
The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5 ± 0.1 mg·kg·day) for 2 weeks before and during 24 h continuous intravenous infusion of LPS (15 μg·kg·h) or saline. Rosi blunted LPS-induced increases in muscle tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA by 70% (<0.05) and 64% (<0.01) respectively. Furthermore, Rosi suppressed the LPS-induced reduction in phosphorylated AKT and phosphorylated Forkhead box O (FOXO) 1 protein, as well as the up-regulation of muscle RING finger 1 (MuRF1; <0.01) mRNA and the LPS-induced increase in 20S proteasome activity (<0.05). Accordingly, LPS reduced the muscle protein:DNA ratio (∼30%, <0.001), which Rosi offset. Increased muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA (<0.001) and muscle lactate accumulation (<0.001) during endotoxaemia were suppressed by Rosi. Thus, pre-treatment with Rosi reduced muscle cytokine accumulation and blunted muscle protein loss and lactate accumulation during endotoxaemia, and at least in part by reducing activation of molecular events known to increase muscle protein breakdown and mitochondrial pyruvate use.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮（Rosi）似乎可在内毒素血症期间对器官功能障碍起到保护作用。我们研究了Rosi在脂多糖（LPS）诱导的内毒素血症期间对骨骼肌蛋白质维持和碳水化合物代谢的潜在益处。在连续24小时静脉输注LPS（15μg·kg·h）或生理盐水之前及期间，将Sprague-Dawley大鼠分为两组，一组喂食标准饲料（对照组），另一组喂食含Rosi（8.5±0.1mg·kg·天）的标准饲料，持续2周。Rosi使LPS诱导的肌肉肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）mRNA增加分别降低了70%（<0.05）和64%（<0.01）。此外，Rosi抑制了LPS诱导的磷酸化AKT和磷酸化叉头框O（FOXO）1蛋白的减少，以及肌肉环指蛋白1（MuRF1；<0.01）mRNA的上调和LPS诱导的20S蛋白酶体活性增加（<0.05）。相应地，LPS降低了肌肉蛋白质与DNA的比率（约30%，<0.001），而Rosi可抵消这一作用。Rosi抑制了内毒素血症期间肌肉丙酮酸脱氢酶激酶4（PDK4）mRNA的增加（<0.001）和肌肉乳酸积累（<0.001）。因此，Rosi预处理可减少内毒素血症期间肌肉细胞因子的积累，减轻肌肉蛋白质损失和乳酸积累，至少部分是通过减少已知会增加肌肉蛋白质分解和线粒体丙酮酸利用的分子事件的激活来实现的。
