TNF? mediates sepsis-induced impairment of basal and leucine-stimulated signaling via S6K1 and eIF4E in cardiac muscle
Autor: | Robert A. Frost, Anne M. Pruznak, Charles H. Lang |
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Rok vydání: | 2005 |
Předmět: |
Male
medicine.medical_specialty P70-S6 Kinase 1 Punctures Biology Biochemistry Rats Sprague-Dawley chemistry.chemical_compound Leucine Sepsis Eukaryotic initiation factor Internal medicine medicine Animals Insulin RNA Messenger Phosphorylation Cecum Molecular Biology Tumor Necrosis Factor-alpha EIF4G Myocardium TOR Serine-Threonine Kinases EIF4E Cardiac muscle Ribosomal Protein S6 Kinases 70-kDa Heart Cell Biology Rats Eukaryotic Initiation Factor-4E Endocrinology medicine.anatomical_structure chemistry Protein Biosynthesis Tumor necrosis factor alpha Eukaryotic Initiation Factor-4G Protein Kinases Signal Transduction |
Zdroj: | Journal of Cellular Biochemistry. 94:419-431 |
ISSN: | 1097-4644 0730-2312 |
Popis: | 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. |
Databáze: | OpenAIRE |
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