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.

Abstract

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 NaHCO 3 . 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 ␣ subunit indicated increased total skeletal muscle IGF-1R number with normal affinity. However, both autophosphorylation of the IGF-1R ␤ 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.

Tumour necrosis factor blockade did not prevent the increase of muscular muscle RING finger-1 and muscle atrophy F-box in arthritic rats

“…Since IGF-I has been reported to inhibit MAFbx expression in the muscles of fasting and diabetic rats (Dehoux et al 2004), the increase in IGF-I in the muscle of arthritic rats should be followed by a decrease in muscular MuRF-1 and MAFbx gene expression. Since this is not the case, there is a possibility that arthritic muscles have become resistant to IGF-I, as has been observed in experimental models of sepsis (Fang et al 2000) and chronic renal failure (Ding et al 1996). This effect can be exerted by muscular TNF-a, since this cytokine acts on muscle cells inducing a state of IGF-I receptor resistance (Broussard et al 2003).…”

The growth hormone–insulin-like growth factor-I axis in chronic kidney disease

“…A study of uremic rats showed a reduction in GHR density in tibial growth plate [58] and low levels of mRNA for hepatic GH receptor [59]. In addition, there is evidence from animal studies that IGF-I resistance also arises from tissue insensitivity caused by a post-receptor defect in IGF-I-mediated signal transduction [60], although the site of the abnormality is controversial [61]. Ding et al [60] studied IGF-IR isolated from skeletal muscle of rats with CRF and reported an increase in IGF-IR number and a decrease in IGF-Iactivated receptor autophosphorylation and tyrosine kinase activity that could not be attributed to IGFBP activity.…”

“…Treatment with recombinant GH can, in part, overcome this resistant state [4]. Furthermore, there is a suggestion that there may also be IGF-I resistance in CKD that additionally contributes to the pathogenesis of growth retardation [5,6]. Perturbations in hypothalamic signaling pathways involving leptin and ghrelin, a ligand of the GH secretagogue receptor, may contribute to cachexia and wasting in CKD [7][8][9][10].…”

Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.

“…In addition to these findings there is evidence of a resistance to GH and IGF-I occurring in uremic muscle. Indeed, a reduced IGF-I and IGF-I mRNA, and a decreased IGF-I receptor tyrosine kinase activity have been observed in muscle from uremic rats (8,9).…”