IGF-I/IGFBP-3 binary complex modulates sepsis-induced inhibition of protein synthesis in skeletal muscle

The present study evaluated the ability of insulin-like growth factor I (IG F-I) complexed with IGF binding protein-3 (IGFBP-3) to modulate the sepsis- induced inhibition of protein synthesis in gastrocnemius. Beginning 16 h af ter the induction of sepsis, either the binary complex or saline was inject ed twice daily via a tail vein, with measurements made 3 and 5 days later. By day 3, sepsis had reduced plasma IGF-I concentrations similar to 50% in saline-treated rats. Administration of the binary complex provided exogenou s IGF-I to compensate for the sepsis-induced diminished plasma IGF-I. Sepsi s decreased rates of protein synthesis in gastrocnemius relative to control s by limiting translational efficiency. Treatment of septic rats with the b inary complex for 5 days attenuated the sepsis-induced inhibition of protei n synthesis and restored translational efficiency to control values. Assess ment of potential mechanisms regulating translational efficiency showed tha t neither the sepsis-induced change in gastrocnemius content of eukaryotic initiation factor 2B (eIF2B), the amount of eIF4E associated with 4E bindin g protein-1 (4E-BP1), nor the phosphorylation state of 4E-BP1 or eIF4E were altered by the binary complex. Overall, the results are consistent with th e hypothesis that decreases in plasma IGF-I are partially responsible for e nhanced muscle catabolism during sepsis.