Insulin fails to stimulate muscle protein synthesis in sepsis despite unimpaired signaling to 4E-BP1 and S6K1.
Induction of sepsis in rats causes an inhibition of protein synthesis in skeletal muscle that is resistant to the stimulatory actions of insulin. To gain a better understanding of the underlying reason for this lack of response, the present study was undertaken to investigate sepsis-induced alterations in insulin signaling to regulatory components of mRNA translation. Experiments were performed in perfused hindlimb preparations from rats 5 days after induction of a septic abscess. Sepsis resulted in a 50% reduction in protein synthesis in the gastrocnemius. Protein synthesis in muscles from septic rats, but not controls, was unresponsive to stimulation by insulin. The insulin-induced hyperphosphorylation response of the translation repressor protein 4E-binding protein 1 (4E-BP1) and of the 70-kDa S6 kinase (S6K1) (1), two targets of insulin action on mRNA translation, was unimpaired in gastrocnemius of septic rats. Hyperphosphorylation of 4E-BP1 in response to insulin resulted in its dissociation from the inactive eukaryotic initiation factor (eIF)4E. 4E-BP1 complex in both control and septic rats. However, assembly of the active eIF4F complex as assessed by the association of eIF4E with eIF4G did not follow the pattern predicted by the increased availability of eIF4E resulting from changes in the phosphorylation of 4E-BP1. Indeed, sepsis caused a dramatic reduction in the amount of eIF4G associated with eIF4E in the presence or absence of insulin. Thus the inability of insulin to stimulate protein synthesis during sepsis may be related to a defect in signaling to a step in translation initiation involved in assembly of an active eIF4F complex.
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Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 10733, USA. TVARY@psu.edu
Jefferson
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Kimball
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D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D039561:Eukaryotic Initiation Factor-4E; D015151:Immunoblotting; D007163:Immunosorbent Techniques; D007328:Insulin / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000032:analysis / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism*; D015398:Signal Transduction
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D039561:Eukaryotic Initiation Factor-4E; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D019893:Ribosomal Protein S6 Kinases