Ding H, Gao X L, Hirschberg R, Vadgama J V, Kopple J D
Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
J Clin Invest. 1996 Feb 15;97(4):1064-75. doi: 10.1172/JCI118499.
The actions of insulin-like growth factor 1 (IGF-1) on protein turnover and of the IGF-1 receptor (IGF-1R) were examined in skeletal muscle of rats with chronic renal failure (CRF) and sham operated (SO), pair-fed controls. Acidemia was prevented in CRF rats with NaHCO3. Serum IGF-1 and skeletal muscle IGF-1 and IGF-1 mRNA were reduced in CRF rats. Dose-response studies revealed impaired stimulation of protein synthesis and suppressed inhibition of protein degradation by IGF-1 in epitrochlearis muscle of CRF rats. Neither IGF-1 analogues with low affinity to IGF binding proteins nor proteinase inhibitors obliterated the IGF-1 resistance. In CRF rats, skeletal muscle IGF-1R mRNA was increased; displacement ligand binding studies and affinity labeling of the IGF-1R alpha subunit indicated increased total skeletal muscle IGF-1R number with normal affinity. However, both autophosphorylation of the IGF-1R beta subunit (i.e., IGF-1R tyrosine kinase) and the IGF-1R tyrosine kinase activity towards exogenous insulin receptor substrate-1, a natural substrate for IGF-1R tyrosine kinase, were reduced in CRF fats. These data indicate that in skeletal muscle of CRF rats there is resistance to the IGF-1 effects on protein synthesis and degradation and decreased IGF-1 and IGF-1 mRNA levels; IGF-1R mRNA and number are increased; but activity of IGF-1R tyrosine kinase is impaired. This postreceptor defect may be a cause of the skeletal muscle resistance to IGF-1 in CRF.
在慢性肾衰竭（CRF）大鼠和假手术（SO）、配对喂养的对照大鼠的骨骼肌中，研究了胰岛素样生长因子1（IGF-1）对蛋白质周转的作用以及IGF-1受体（IGF-1R）的情况。用碳酸氢钠预防CRF大鼠的酸血症。CRF大鼠的血清IGF-1、骨骼肌IGF-1和IGF-1 mRNA水平降低。剂量反应研究显示，CRF大鼠肱三头肌中IGF-1对蛋白质合成的刺激受损，对蛋白质降解的抑制作用受到抑制。对IGF结合蛋白亲和力低的IGF-1类似物和蛋白酶抑制剂均不能消除IGF-1抵抗。在CRF大鼠中，骨骼肌IGF-1R mRNA增加；IGF-1R置换配体结合研究和IGF-1Rα亚基的亲和标记表明，骨骼肌IGF-1R总数增加，亲和力正常。然而，CRF大鼠中IGF-1Rβ亚基的自磷酸化（即IGF-1R酪氨酸激酶）以及IGF-1R酪氨酸激酶对外源胰岛素受体底物-1（IGF-1R酪氨酸激酶的天然底物）的活性均降低。这些数据表明，在CRF大鼠的骨骼肌中，存在对IGF-1对蛋白质合成和降解作用的抵抗，IGF-1和IGF-1 mRNA水平降低；IGF-1R mRNA和数量增加；但IGF-1R酪氨酸激酶活性受损。这种受体后缺陷可能是CRF大鼠骨骼肌对IGF-1抵抗的原因。
