Abstract
The aim of this study was to evaluate the effect of insulin like growth factor-I (rhIGF-I) in complex with binding protein 3 (IGFBP 3) compared to the effect of free IGF-I on muscle protein biosynthesis in undernourished animals. Three groups of female Sprague-Dawley rats (200 g) were initially semi-starved for 3 days and then treated with saline (controls), rhIGF-I (1 microg g-1) or equimolar amounts of rhIGF-I/rhIGFBP-3 complex (5 microg g-1) i.v. twice daily for 3 days during continuous semistarvation. Protein metabolism in hind limb skeletal muscle was studied by incorporation of L-[14C-U]phenylalanine into proteins, western blot determination of translation initiation factors involved in the binding of the 40S ribosomal subunit to mRNA, and quantification of mRNA content for IGF-I, IGF-IR and GH-R. Plasma measurements of insulin, IGF-I and amino acids were also performed. rhIGF-I/rhIGFBP-3, but not rhIGF-I alone, stimulated protein synthesis by 177 +/- 26% (P </= 0.05) in semi-starved rats. This stimulation was associated with dissociation of the 4E-BP1. eIF-4E complex, implicating increased binding of the 40S ribosomal subunit to mRNA, and hence increased initiation of protein synthesis in these animals. Muscle content of IGF-I mRNA was reduced in semi-starved animals, whereas IGF-I receptor mRNA was unaltered despite food restriction. Plasma concentration of IGF-I was 20% (P </= 0.05) higher in rhIGF-I/rhIGFBP-3 treated animals as compared to rats treated with saline or free IGF-I. Plasma concentrations of amino acids were increased in rhIGF-I/rhIGFBP-3 treated animals (P </= 0.05 vs. semi-starved controls). rhIGF-I/rhIGFBP-3 (SomatoKine) was a significant stimulator of muscle protein synthesis in chronically semi-starved animals whereas IGF-I alone failed to increase protein synthesis during the same experimental conditions. This stimulation was because of increased initiation of translation, likely induced by more physiologic concentrations/kinetics of plasma IGF-I and amino acids following rhIGF-I/rhIGFBP-3 treatment, compared to IGF-I in its free form.
Published Version
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