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

• Published in: The Journal of clinical investigation 1996-02, Vol.97 (4), p.1064-1075
• Main Authors: Ding, H, Gao, X L, Hirschberg, R, Vadgama, J V, Kopple, J D
• Format: Article
• Language: English
• Subjects: Animals; Insulin-Like Growth Factor I - pharmacology; Kidney Failure, Chronic - metabolism; Male; Muscle Proteins - metabolism; Muscles - metabolism; Phosphorylation; Protease Inhibitors - pharmacology; Protein-Tyrosine Kinases - metabolism; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1 - metabolism; Signal Transduction
• ISSN: 0021-9738
• 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.