Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1

Abstract

Induction of sepsis in rats causes an inhibition of protein synthesis in skeletal muscle that is resistant to the stimulatory actions of insulin. To gain a better understanding of the underlying reason for this lack of response, the present study was undertaken to investigate sepsis-induced alterations in insulin signaling to regulatory components of mRNA translation. Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess. Sepsis resulted in a 50% reduction in protein synthesis in the gastrocnemius. Protein synthesis in muscles from septic rats, but not controls, was unresponsive to stimulation by insulin. The insulin-induced hyperphosphorylation response of the translation repressor protein 4E-binding protein 1 (4E-BP1) and of the 70-kDa S6 kinase (S6K1) (1), two targets of insulin action on mRNA translation, was unimpaired in gastrocnemius of septic rats. Hyperphosphorylation of 4E-BP1 in response to insulin resulted in its dissociation from the inactive eukaryotic initiation factor (eIF)4E. 4E-BP1 complex in both control and septic rats. However, assembly of the active eIF4F complex as assessed by the association of eIF4E with eIF4G did not follow the pattern predicted by the increased availability of eIF4E resulting from changes in the phosphorylation of 4E-BP1. Indeed, sepsis caused a dramatic reduction in the amount of eIF4G associated with eIF4E in the presence or absence of insulin. Thus the inability of insulin to stimulate protein synthesis during sepsis may be related to a defect in signaling to a step in translation initiation involved in assembly of an active eIF4F complex.

Regulation of Muscle Protein Synthesis in Neonatal Pigs During Prolonged Endotoxemia

“…Because insulin resistance has been implicated in the reduction in protein synthesis in different adult models of sepsis (26,45), we speculate that the fact that muscle protein synthesis was only modestly reduced in this neonatal model of endotoxemia may be ascribed to the unique sensitivity and responsiveness of neonatal muscle protein synthesis to insulin and amino acids. Because of the endogenous production of insulin induced by glucose and amino acid infusion, the enhanced sensitivity of neonatal muscle protein synthesis to these anabolic agents (17,18,20,22), and the lack of apparent insulin resistance in this model, it appears that the elevation in insulin and/or amino acids to fed levels (18,22,27) may have circumvented some of the catabolic effects induced by the septic-like state (15) and blunted the reduction in muscle protein synthesis by endotoxin.…”

“…1B). This step is modulated by eIF2 (26), whose activity is regulated by the guanine nucleotide exchange factor, eIF2B (25,26). The second well-characterized regulatory process in peptidechain initiation involves the binding of mRNA to the 43S preinitiation complex via mediation of the assembly of the eIF4F complex of proteins (Fig.…”

“…In adult rats, LPS has been found to profoundly depress translation initiation in muscle by decreasing eIF2B activity, 4E-BP1 phosphorylation, and eIF4G·eIF4E complex assembly, and increasing the association of the repressor, 4E-BP1, with eIF4E (6,26). When challenged acutely with endotoxin, neonatal animals also reduce the activation of translation initiation factors that modulate the mRNA binding step in muscle (30).…”

“…Because of the endogenous production of insulin induced by glucose and amino acid infusion, the enhanced sensitivity of neonatal muscle protein synthesis to these anabolic agents (17,18,20,22), and the lack of apparent insulin resistance in this model, it appears that the elevation in insulin and/or amino acids to fed levels (18,22,27) may have circumvented some of the catabolic effects induced by the septic-like state (15) and blunted the reduction in muscle protein synthesis by endotoxin. The response of muscle protein synthesis to insulin in adult septic rats is characterized by both a decreased sensitivity and a decreased maximal responsiveness compared with control rats (26). More detailed study is required to determine whether insulin modulates muscle protein synthesis in neonates during septic states.…”

“…Translation initiation in neonatal muscle is enhanced by insulin and amino acids in normal conditions (24,25,27). Studies in adult animals have shown that translation initiation in glycolytic muscles is profoundly reduced during sepsis by suppressing both mRNA and met-tRNA i binding to the 40S ribosomal complex, and those changes included a decreased eIF4G•eIF4E complex formation (26) and eIF2B activity (6,16,26). In our study in neonatal animals, PKB phosphorylation was not affected by LPS in liver or muscle, suggesting a lack of effect of endotoxin on the early steps of the insulin signal transduction pathway.…”