Sepsis induces the loss of
muscle proteins by impairing skeletal muscle
protein synthesis through an inhibition of
messenger RNA (mRNA) translation initiation.
Amino acids and
Leu (Leu) in particular stimulate mRNA translation initiation. The experiments were designed to test the effects of Leu on potential signal transduction pathways that may be important in accelerating mRNA translation initiation in skeletal muscle of rats with chronic (5-6 d) septic
intra-abdominal abscess. Gastrocnemius from male Sprague Dawley rats gavaged with Leu or water were sampled 5-6 d following development of an intra-abdominal sterile or septic
abscess. Gavage with Leu stimulated
protein synthesis and enhanced the assembly of the active eukaryotic
initiation factor (eIF)4G-eIF4E complex. Increased assembly of the active eIF4G-eIF4E complex was associated with a robust rise in phosphorylation of
eIF4G(Ser(1108)) and a decreased assembly of inactive
eIF4E binding protein-1 (4E-BP1)-eIF4E complex in both sterile inflammatory and septic rats. The reduced assembly of 4E-BP1-eIF4E complex was associated with an increase in phosphorylation of 4E-BP1 in the gamma-form following Leu gavage. Phosphorylation of 70-kDa
ribosomal protein S6 kinase on Thr(389) was also increased following Leu gavage, as well as the phosphorylation of
mammalian target of rapamycin on Ser(2448) or Ser(2481). In contrast, phosphorylation of
protein kinase B (PKB) on Thr(308) or Ser(473) was not augmented following Leu gavage in septic rats. We conclude that Leu stimulates a PKB-independent signal pathway elevating the eIF4G-eIF4E complex assembly through increased phosphorylation of
eIF4G and decreased association of 4E-BP1 with
eIF4E in skeletal muscle during
sepsis.