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1 Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA, USA
* To whom correspondence should be addressed. E-mail: tvary{at}psu.edu.
Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius that is not observed in rats with a sterile abscess. The inhibition is associated with an impaired mRNA translation initiation that can be ameliorated by elevating insulin-like growth factor-I, but not insulin. The present study investigated the ability of IGF-I signaling to stimulate protein synthesis in gastrocnemius by accelerating mRNA translation initiation. Experiments were performed in perfused hindlimb preparations from rats 5 days following induction of a septic abscess. Protein synthesis in gastrocnemius from septic rats was accelerated 2-fold by addition of IGF-I (10 nM) to perfusate. IGF-I increased the phosphorylation of the translation repressor protein, 4EBP1. Hyperphosphorylation of 4E-BP1 in response to IGF-I resulted in its dissociation from the inactive eIF4E.4E-BP1 complex. Assembly of the active eIF4F complex (as assessed by the association eIF4G with eIF4E) was increased 2-fold by IGF-I in the perfusate. In addition, phosphorylation of eIF4G and S6K1 was also enhanced by IGF-I. Activation of mTOR an upstream kinase implicated in phosphorylating both 4E-BP1 and S6K1 was also observed. Thus, the ability of IGF-I to accelerating protein synthesis during sepsis may be related to a stimulation of signaling to multiple steps in translation initiation with an ensuing increased hosphorylation of eIF4G, eIF4E availability, as well as S6K1 phosphorylation.
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