title: TNFalpha mediates sepsis-induced impairment of basal and leucine-stimulated signaling via S6K1 and eIF4E in cardiac muscle.
abstract: Decreased translation initiation adversely impacts protein synthesis and contributes to the myocardial dysfunction produced by sepsis. Therefore, the purpose of the present study was to identify sepsis-induced changes in signal transduction pathways known to regulate translation initiation in cardiac muscle and to determine whether the stimulatory effects of leucine can reverse the observed defects. To address this aim, sepsis was produced by cecal ligation and puncture (CLP) in anesthetized rats and the animals studied in the fasted condition 24 h later. Separate groups of septic and time-matched control rats also received an oral gavage of leucine. To identify potential mechanisms responsible for regulating cap-dependent mRNA translation in cardiac muscle, several eukaryotic initiation factors (eIFs) were examined. Under basal conditions, hearts from septic rats demonstrated a redistribution of the rate-limiting factor eIF4E due to increased binding of the translational repressor 4E-BP1 with eIF4E. However, this change was independent of an alteration in the phosphorylation state of 4E-BP1. The phosphorylation of mTOR, S6K1, the ribosomal protein (rp) S6, and eIF4G was not altered in hearts from septic rats under basal conditions. In control rats, leucine failed to alter eIF4E distribution but increased the phosphorylation of S6K1 and S6. In contrast, in hearts from septic rats leucine acutely reversed the alterations in eIF4E distribution. However, the ability of leucine to increase S6K1 and rpS6 phosphorylation in septic hearts was blunted. Sepsis increased the content of tumor necrosis factor (TNF)-alpha in heart and pre-treatment of rats with a TNF antagonist prevented the above-mentioned sepsis-induced changes. These data indicate that oral administration of leucine acutely reverses sepsis-induced alterations eIF4E distribution observed under basal conditions but the anabolic actions of this amino acid on S6K1 and rpS6 phosphorylation remain blunted, providing evidence for a leucine resistance. Finally, TNFalpha, either directly or indirectly, appears to mediate the sepsis-induced defects in myocardial translation initiation.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. clang@psu.edu
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
authors.forename: Anne M
authors.initials: AM
authors.lastname: Pruznak
authors.forename: Robert A
authors.initials: RA
authors.lastname: Frost
mesh_terms: D000818:Animals; D002432:Cecum / Q000473:pathology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000097:blood; D007930:Leucine / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism; D011677:Punctures; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D018805:Sepsis / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D007328:Insulin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D007930:Leucine