IMPAIRED ACTIONS OF INSULIN-LIKE-GROWTH-FACTOR-1 ON PROTEIN-SYNTHESISAND DEGRADATION IN SKELETAL-MUSCLE OF RATS WITH CHRONIC-RENAL-FAILURE- EVIDENCE FOR A POSTRECEPTOR DEFECT

The actions of insulin-like growth factor 1 (IGF-1) on protein turnove r 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 IG F-1 and skeletal muscle IGF-1 and IGF-1 mRNA were reduced in CRF rats. Dose-response studies revealed impaired stimulation of protein synthe sis and suppressed inhibition of protein degradation by IGF-1 in epitr ochlearis muscle of CRF Fats. Neither IGF-1 analogues with low affinit y to IGF binding proteins nor proteinase inhibitors obliterated the IG F-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 k inase activity towards exogenous insulin receptor substrate-1, a natur al substrate for IGF-1R tyrosine kinase, were reduced in CRF rats. The se data indicate that in skeletal muscle of CRF rats there is resistan ce to the IGF-1 effects on protein synthesis and degradation and decre ased IGF-1 and IGF-1 mRNA levels; IGF-1R mRNA and number are increased : but activity of IGF-1R tyrosine kinase is impaired. This postrecepto r defect may be a cause of the skeletal muscle resistance to IGF-1 in CRF.