Hormone, cytokine, and nutritional regulation of sepsis-induced increases in atrogin-1 and MuRF1 in skeletal muscle
Hormone, cytokine, and nutritional regulation of sepsis-induced increases in atrogin-1 and MuRF1 in skeletal muscle
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DOI：
10.1152/ajpendo.00359.2006
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发表时间：
2007-02-01
影响因子：
5.1
通讯作者：
Lang, Charles H.
中科院分区：
文献类型：
--
作者：
Frost, Robert A.;Nystrom, Gerald J.;Lang, Charles H.
各种萎缩刺激增加两种肌肉特异性E3连接酶，肌肉环指1（MuRF 1）和atrogin-1，这些“atrogenes”的敲除小鼠显示对去神经诱导的萎缩的抵抗力。本研究确定了atrogin-1和MuRF 1 mRNA的增加是否是由成年大鼠内源性糖皮质激素或炎性细胞因子的过度产生介导的，以及atrogene的表达是否可以被合成代谢剂如胰岛素样生长因子（IGF）-I和营养信号氨基酸亮氨酸下调。内毒素可使腓肠肌atrogin-1和MuRF 1 mRNA表达呈剂量和时间依赖性上调。此外，盲肠结扎和穿孔产生的腹膜炎增加atrogin-1和MuRF 1 mRNA在腓肠肌（但不是比目鱼肌或心脏）的8小时，这是持续72和24小时，分别。而脓毒症诱导的atrogin-1表达的增加被IGF-I完全阻止，增加的MuRF 1没有改变。与IGF-I效应相反，脓毒症诱导的两种atrogenes mRNA的增加对亮氨酸的急性或重复给药均无反应。而外源性输注TNF-α增加atrogin-1和MuRF 1在腓肠肌，预处理脓毒症大鼠与TNF拮抗剂TNF-结合蛋白并没有阻止任何atrogen的表达增加。同样，地塞米松增加atrogene的表达，预处理与糖皮质激素受体拮抗剂RU-486未能改善脓毒症引起的atrogin-1和MuRF 1的增加。因此，在体内条件下，在成熟的成年大鼠，脓毒症诱导的增加肌肉atrogin-1和MuRF 1 mRNA出现糖皮质激素和TNF的独立性，是无反应的亮氨酸。
Various atrophic stimuli increase two muscle-specific E3 ligases, muscle RING finger 1 (MuRF1) and atrogin-1, and knockout mice for these "atrogenes" display resistance to denervation-induced atrophy. The present study determined whether increased atrogin-1 and MuRF1 mRNA are mediated by overproduction of endogenous glucocorticoids or inflammatory cytokines in adult rats and whether atrogene expression can be downregulated by anabolic agents such as insulin-like growth factor (IGF)-I and the nutrient-signaling amino acid leucine. Both atrogin-1 and MuRF1 mRNA in gastrocnemius was upregulated dose and time dependently by endotoxin. Additionally, peritonitis produced by cecal ligation and puncture increased atrogin-1 and MuRF1 mRNA in gastrocnemius ( but not soleus or heart) by 8 h, which was sustained for 72 and 24 h, respectively. Whereas the sepsis-induced increase in atrogin-1 expression was completely prevented by IGF-I, the increased MuRF1 was not altered. In contrast to the IGF-I effect, the sepsis-induced increased mRNA of both atrogenes was unresponsive to either acute or repetitive administration of leucine. Whereas exogenous infusion of TNF-alpha increased atrogin-1 and MuRF1 in gastrocnemius, pretreatment of septic rats with the TNF antagonist TNF-binding protein did not prevent increased expression of either atrogene. Similarly, whereas dexamethasone increased atrogene expression, pretreatment with the glucocorticoid receptor antagonist RU-486 failed to ameliorate the sepsis-induced increase in atrogin-1 and MuRF1. Thus, under in vivo conditions in mature adult rats, the sepsis-induced increase in muscle atrogin-1 and MuRF1 mRNA appears both glucocorticoid and TNF independent and is unresponsive to leucine.