Sepsis and inflammatory insults downregulate IGFBP-5, but not IGFBP-4, in skeletal muscle via a TNF-dependent mechanism
Sepsis and inflammatory insults downregulate IGFBP-5, but not IGFBP-4, in skeletal muscle via a TNF-dependent mechanism
复制标题
DOI：
10.1152/ajpregu.00684.2005
复制
发表时间：
2006-04-01
影响因子：
2.8
通讯作者：
Frost, RA
中科院分区：
文献类型：
--
作者：
Lang, CH;Krawiec, BJ;Frost, RA
本研究的目的是确定诱导肌肉萎缩的分解代谢刺激是否改变胰岛素样生长因子结合蛋白（IGFBP）-4和-5的mRNA丰度，如果是这样，确定这种变化的生理机制。内毒素（LPS）和脓毒症产生的分解代谢损伤降低IGFBP-5 mRNA的时间和剂量依赖性在腓肠肌。这种减少并不是由于肌肉废用，因为后肢制动增加IGFBP-5。连续输注非致死剂量的肿瘤坏死因子-α（TNF-α）可使IGFBP-5 mRNA降低70%，而用中和TNF结合蛋白预处理脓毒症大鼠可完全阻止肌肉IGFBP-5的降低。加入LPS或TNF-α培养的C2Cl 2成肌细胞也降低IGFBP-5的表达。虽然外源性生长激素（GH）增加IGFBP-5 mRNA的2倍，从对照组大鼠的肌肉，肌肉从脓毒症动物生长激素耐药，并没有这样的海拔检测。相反，外源性给予IGF-I作为IGF-I/IGFBP-3组成的二元复合物的一部分，在对照和脓毒症肌肉中产生了IGFBP-5 mRNA的相当增加。IGF-I mRNA含量的同时测定揭示了在同一肌肉中响应于LPS、脓毒症、TNF-α和GH处理的IGF-I和IGFBP- 5 mRNA之间的正线性关系。虽然地塞米松降低肌肉IGFBP-5，与糖皮质激素受体拮抗剂RU 486的大鼠预处理不能防止脓毒症诱导的IGFBP-5 mRNA的减少。相反，肌肉IGFBP-4 mRNA丰度没有显着改变LPS，脓毒症，或后肢制动。总之，这些数据表明，各种炎症损伤通过TNF依赖性糖皮质激素非依赖性机制降低肌肉IGFBP-5 mRNA，而不改变IGFBP-4。最后，IGF-I似乎是在正常和分解代谢条件下肌肉中IGFBP-5基因表达的显性正调节剂。
The purpose of the present study was to determine whether catabolic stimuli that induce muscle atrophy alter the muscle mRNA abundance of insulin-like growth factor binding protein (IGFBP)-4 and -5, and if so determine the physiological mechanism for such a change. Catabolic insults produced by endotoxin (LPS) and sepsis decreased IGFBP-5 mRNA time- and dose-dependently in gastrocnemius muscle. This reduction did not result from muscle disuse because hindlimb immobilization increased IGFBP-5. Continuous infusion of a nonlethal dose of tumor necrosis factor-alpha (TNF-alpha) decreased IGFBP-5 mRNA 70%, whereas pretreatment of septic rats with a neutralizing TNF binding protein completely prevented the reduction in muscle IGFBP-5. The addition of LPS or TNF-alpha to cultured C2Cl2 myoblasts also decreased IGFBP-5 expression. Although exogenously administered growth hormone (GH) increased IGFBP-5 mRNA 2-fold in muscle from control rats, muscle from septic animals was GH resistant and no such elevation was detected. In contrast, exogenous administration of IGF-I as part of a binary complex composed of IGF-I/IGFBP-3 produced comparable increases in IGFBP-5 mRNA in both control and septic muscle. Concomitant determinations of IGF-I mRNA content revealed a positive linear relationship between IGF-I and IGFBP- 5 mRNA in the same muscle in response to LPS, sepsis, TNF-alpha, and GH treatment. Although dexamethasone decreased muscle IGFBP-5, pretreatment of rats with the glucocorticoid receptor antagonist RU486 did not prevent the sepsis-induced decrease in IGFBP-5 mRNA. In contrast, muscle IGFBP-4 mRNA abundance was not significantly altered by LPS, sepsis, or hindlimb immobilization. In summary, these data demonstrate that various inflammatory insults decrease muscle IGFBP-5 mRNA, without altering IGFBP-4, by a TNF-dependent glucocorticoid-independent mechanism. Finally, IGF-I appears to be a dominant positive regulator of IGFBP-5 gene expression in muscle under both normal and catabolic conditions.