Impaired actions of insulin-like growth factor 1 on protein synthesis and degradation in skeletal muscle of rats with chronic renal failure - Evidence for a postreceptor defect
Impaired actions of insulin-like growth factor 1 on protein synthesis and degradation in skeletal muscle of rats with chronic renal failure - Evidence for a postreceptor defect
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DOI：
10.1172/jci118499
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发表时间：
1996-02-15
影响因子：
15.9
通讯作者：
Kopple, JD
中科院分区：
文献类型：
--
作者：
Ding, H;Gao, XL;Kopple, JD
在慢性肾衰竭（CRE）和假手术（SO）、成对喂养对照大鼠的骨骼肌中检查了胰岛素样生长因子1（IGF-1）对蛋白质周转和IGF-1受体（IGF-1 R）的作用。用NaHCO 3预防CRF大鼠的酸血症。CRF大鼠血清IGF-1和骨骼肌IGF-1及其mRNA水平降低。剂量反应研究显示，CRF脂肪的滑车上肌中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都不能消除IGF-1抗性。在CRF大鼠，骨骼肌IGF-1 R mRNA增加：置换配体结合研究和IGF-1 R ru亚基的亲和标记表明，增加了总骨骼肌IGF-1 R的数量与正常的亲和力。然而，IGF-1 R β亚基的自身磷酸化（即，在慢性肾衰竭大鼠中，胰岛素样生长因子-1受体酪氨酸激酶）和胰岛素样生长因子-1受体酪氨酸激酶对外源性胰岛素受体底物-1（胰岛素样生长因子-1受体酪氨酸激酶的天然底物）的活性降低。这些数据表明，在CRF大鼠骨骼肌中，存在对IGF-1对蛋白质合成和降解的影响的抵抗，IGF-1和IGF-1 mRNA水平降低; IGF-1 R mRNA和数量增加：但IGF-1 R酪氨酸激酶活性受损。这种受体后缺陷可能是CRF患者骨骼肌对IGF-1抵抗的原因之一。
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 (CRE) 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 Fats. 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 ru 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 rats. 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.