Lang Charles H, Vary Thomas C, Frost Robert A
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Endocrinology. 2003 Sep;144(9):3922-33. doi: 10.1210/en.2002-0192.
This study examined whether the acute elevation of IGF-binding protein-1 (IGFBP-1) decreases the plasma free IGF-I concentration and alters in vivo rates of muscle protein synthesis and glucose uptake. The plasma concentration of human IGFBP-1 was increased to approximately 95 ng/ml in conscious catheterized rats infused iv with human IGFBP-1 for 4 h. Infusion of IGFBP-1 also increased the concentration of endogenous (e.g. rat) IGFBP-1 in the blood, and this response was associated with a 2- to 3-fold elevation of IGFBP-1 mRNA in liver and kidney. IGFBP-1 did not significantly alter the plasma concentration of total IGF-I, but decreased circulating free IGF-I levels by about 50%. IGFBP-1 decreased protein synthesis in the predominantly fast-twitch gastrocnemius muscle (20%), and this change resulted from a decreased translational efficiency that was associated with a decreased phosphorylation of S6K1, but not 4E-BP1. Complementary studies demonstrated that IGFBP-1 also decreased the rates of protein synthesis under basal conditions and in response to stimulation by IGF-I when added in vitro to the fast-twitch epitrochlearis muscle. In contrast, IGFBP-1 did not alter in vivo-determined rates of protein synthesis in the slow-twitch soleus muscle, heart, liver, or kidney. The infusion of IGFBP-1 did not significantly alter the plasma glucose or lactate concentration or the whole body rate of glucose production or disposal. The above-mentioned changes were not mediated indirectly by changes in the plasma insulin or corticosterone concentrations, decreased high energy phosphate content in muscle, or hepatoxicity produced by the infused IGFBP-1. These results demonstrate that acute in vivo elevation in IGFBP-1, of the magnitude observed in various catabolic conditions, is capable of selectively decreasing protein synthesis in fast-twitch skeletal muscle and up-regulating the hepatic and renal syntheses of IGFBP-1 per se. Hence, elevations in circulating and tissue levels of IGFBP-1 may be an important mediator for the muscle catabolism observed in various stress conditions.
本研究检测了胰岛素样生长因子结合蛋白-1（IGFBP-1）的急性升高是否会降低血浆游离IGF-I浓度，并改变体内肌肉蛋白质合成和葡萄糖摄取的速率。通过对有意识的插管大鼠静脉输注人IGFBP-1 4小时，将人IGFBP-1的血浆浓度提高到约95 ng/ml。输注IGFBP-1还会增加血液中内源性（如大鼠）IGFBP-1的浓度，这种反应与肝脏和肾脏中IGFBP-1 mRNA升高2至3倍有关。IGFBP-1不会显著改变总IGF-I的血浆浓度，但会使循环游离IGF-I水平降低约50%。IGFBP-1使主要为快肌的腓肠肌中的蛋白质合成减少（20%），这种变化是由于翻译效率降低所致，这与S6K1磷酸化减少有关，但与4E-BP1无关。补充研究表明，当在体外添加到快肌的肱三头肌中时，IGFBP-1在基础条件下以及对IGF-I刺激的反应中也会降低蛋白质合成速率。相比之下，IGFBP-1不会改变体内测定的慢肌比目鱼肌、心脏、肝脏或肾脏中的蛋白质合成速率。输注IGFBP-1不会显著改变血浆葡萄糖或乳酸浓度，也不会改变全身葡萄糖生成或处置的速率。上述变化并非由血浆胰岛素或皮质酮浓度的变化、肌肉中高能磷酸含量的降低或输注的IGFBP-1产生的肝毒性间接介导。这些结果表明，在各种分解代谢条件下观察到的IGFBP-1急性体内升高幅度，能够选择性地降低快肌骨骼肌中的蛋白质合成，并上调IGFBP-1本身的肝脏和肾脏合成。因此，IGFBP-1循环水平和组织水平的升高可能是各种应激条件下观察到的肌肉分解代谢的重要介质。
