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1 Department of Cellular & Molecular Physiology and Surgery, Pennsylvania State University College of Medicine, Hershey, PA, USA
* To whom correspondence should be addressed. E-mail: clang{at}psu.edu.
Polymicrobial sepsis impairs skeletal muscle protein synthesis which results from an impairment in translation initiation under basal conditions. The purpose of the present study was to test the hypothesis that sepsis also impairs the anabolic response to amino acids, specifically leucine (Leu). Sepsis was induced by cecal ligation and puncture and 24 h thereafter septic and time-matched nonseptic rats were orally administered either Leu or saline (Sal). The gastrocnemius was removed 20 min later to assess protein synthesis and signaling components important in peptide-chain initiation. Oral Leu increased muscle protein synthesis in nonseptic rats. However, Leu was unable to increase protein synthesis in muscle from septic rats and synthetic rates remained below those observed in the nonseptic+Sal group. In the nonseptic+Leu group phosphorylation of 4E-BP1 in muscle was markedly increased, compared to values from time-matched saline-treated nonseptic rats. This change was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E.4E-BP1 to the active eIF4E.eIF4G complex. In septic rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E distribution were completely abrogated. Sepsis also antagonized the Leuinduced increase in phosphorylation of S6K1 and the ribosomal protein S6. Moreover, sepsis attenuated the Leu-induced phosphorylation of mTOR and eIF4G. The ability of sepsis to inhibit the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin, insulin-like growth factor (IGF)-I or Leu between groups. In contrast, the ability of exogenous IGF-I to stimulate the same signaling components pertaining to translation initiation was not impaired by sepsis. Hence, sepsis produces a relatively specific leucine resistance in skeletal muscle that impairs the ability of this amino acid to stimulate translation intiation and protein synthesis.
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