title: Sepsis-induced suppression of skeletal muscle translation initiation mediated by tumor necrosis factor alpha.
abstract: Inhibition of translational efficiency is responsible at least in part for the sepsis-induced decrease in protein synthesis observed in skeletal muscle. Moreover, infusion of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) into naive rats produces a comparable decrement. Therefore, the purpose of the present study was to determine whether inhibition of TNF action under in vivo conditions could prevent the sepsis-induced decrease in translation initiation observed in the postabsorptive state. To address this aim, sepsis was produced by cecal ligation and puncture (CLP) and rats were studied in the fasted condition 20 to 24 hours thereafter. Both septic and time-matched nonseptic control rats were pretreated with TNF-binding protein (TNF(BP)) before CLP or sham surgery to neutralize endogenously produced TNF. Sepsis altered the distribution of eukaryotic initiation factor 4E (eIF4E) in the gastrocnemius by increasing the amount associated with 4E-BP1 (inactive complex) and decreasing the amount bound to eIF4G (active complex). This change in eIF4E availability was associated with a decreased phosphorylation of 4E-BP1. Furthermore, the phosphorylation of ribosomal protein S6 and mammalian target of rapamycin (mTOR) was also decreased in the gastrocnemius from septic rats. Pretreatment of septic rats with TNF(BP) largely ameliorated the altered distribution of eIF4E as well as the reduced phosphorylation of 4E-BP1, S6, and mTOR. In contrast, sepsis did not change either the total amount or the phosphorylation state of eIF2alpha or eIF2Bepsilon. Furthermore, no sepsis-induced change in eIFs was detected in the slow-twitch soleus muscle. The ability of TNF(BP) to prevent the sepsis-induced alterations in translation initiation was independent of change in plasma insulin and proportional to the insulinlike growth factor I content in blood and muscle but was associated with a reduction in plasma corticosterone. Hence, the decreased constitutive protein synthesis observed in fast-twitch skeletal muscle in response to peritonitis is mediated by a TNF-dependent mechanism affecting mTOR regulation of translation initiation.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. clang@psu.edu
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Frost
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D015151:Immunoblotting; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D038601:Ribosomal Protein S6; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases