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首页> 外文期刊>American Journal of Physiology >Sepsis and inflammatory insults downregulate IGFBP-5, but not IGFBP-4, in skeletal muscle via a TNF-dependent mechanism.
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Sepsis and inflammatory insults downregulate IGFBP-5, but not IGFBP-4, in skeletal muscle via a TNF-dependent mechanism.

机译：败血症和炎性损伤通过TNF依赖性机制下调骨骼肌中的IGFBP-5，而不是IGFBP-4。

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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 C(2)C(12) 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 elevationwas 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.
机译：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的肌肉mRNA丰度，如果是，则确定这种变化的生理机制。内毒素（LPS）和败血症产生的分解代谢性损伤降低腓肠肌中IGFBP-5 mRNA的时间和剂量依赖性。这种减少不是由于肌肉废止引起的，因为后肢固定增加了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％，而败血症大鼠中和性TNF结合蛋白的预处理则完全阻止了肌肉IGFBP-5的降低。向培养的C（2）C（12）成肌细胞中添加LPS或TNF-α也降低了IGFBP-5的表达。尽管外源施用的生长激素（GH）使对照大鼠肌肉中的IGFBP-5 mRNA升高了2倍，但脓毒症动物的肌肉却具有GH抗性，并且未检测到这种升高。相反，作为对照的由IGF-1 / IGFBP-3组成的二元复合物的一部分，外源给予IGF-1在对照和脓毒性肌肉中产生了可比的IGFBP-5mRNA增加。对IGF-I mRNA含量的同时测定显示，同一肌肉中对LPS，败血症，TNF-α和GH的治疗呈正线性关系，IGF-1和IGFBP-5 mRNA之间呈正线性关系。尽管地塞米松降低了肌肉IGFBP-5，但是用糖皮质激素受体拮抗剂RU486预处理大鼠并不能阻止败血症诱导的IGFBP-5 mRNA的降低。相比之下，LPS，败血症或后肢固定不会明显改变肌肉IGFBP-4 mRNA的丰度。总而言之，这些数据表明，各种炎性损伤通过不依赖TNF的糖皮质激素依赖性机制，在不改变IGFBP-4的情况下降低了肌肉IGFBP-5 mRNA。最后，在正常和分解代谢条件下，IGF-1似乎都是肌肉中IGFBP-5基因表达的主要正调节剂。

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