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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure
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Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure

机译：酰化生长素释放肽治疗可正常化大鼠慢性心力衰竭中骨骼肌线粒体的氧化能力和AKT磷酸化

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Abstract Background Chronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models. Methods We investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post-myocardial infarction CHF model. Results No statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham-operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level ( P < 0.05), associated with activating nuclear translocation of pro-inflammatory transcription factor nuclear factor-???oB. AG completely normalized all alterations ( P < 0.05 vs P, P = NS vs sham-operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG-dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group. Conclusions Sustained peripheral AG treatment with preserved food intake normalizes a CHF-induced tissue-specific cluster of skeletal muscle mitochondrial dysfunction, pro-inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF-associated muscle catabolic alterations, with potential positive impact on patient outcome.
机译：摘要背景慢性心力衰竭（CHF）与骨骼肌异常有关，导致运动不耐受，肌肉丢失以及对患者预后的负面影响。已经提出了线粒体功能障碍的主要作用，其可能由全身和组织炎症引起，并进一步导致低胰岛素信号传导。在健康和患病的啮齿动物模型中，胃激素ghrelin（AG）的酰化形式均可改善线粒体的氧化能力和胰岛素信号传导。方法我们研究了渗透性微型泵（50 nmol / kg /天，连续28天）与安慰剂（P）相比，连续皮下注射（AG）对骨骼肌线粒体酶活性，线粒体生物发生调节因子转录表达和胰岛素信号传导的影响。啮齿动物心肌梗死后CHF模型。结果三组之间在累积食物摄入量上没有观察到统计学上的显着差异（NS）。与假手术相比，P具有较低的线粒体酶活性，线粒体生物发生调节因子转录和AKT水平的胰岛素信号激活（P <0.05），与促炎性转录因子核因子-oB的核易位有关。 AG完全标准化了所有改变（P <0.05 vs P，P = NS vs假手术）。直接的AG活动得到体外C2C12肌管实验的大力支持，该实验显示了AG依赖的线粒体酶活性的刺激。在任何一组的肝脏中，均未观察到线粒体参数和胰岛素信号的变化。结论维持外周血AG摄入和保持食物摄入可使CHF诱导的骨骼肌线粒体功能异常，促炎性变化和胰岛素信号减少的组织特异性簇正常化。因此，AG是治疗CHF相关性肌肉分解代谢改变的潜在疗法，对患者预后可能产生积极影响。

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