Abstract
In adults, protein synthesis in skeletal muscle is reduced by as much as 50% after a septic challenge, and is associated with repression of translation initiation. Neonates are highly anabolic and their muscle protein synthesis rates are elevated and uniquely sensitive to amino acid and insulin stimulation. In the present study, neonatal piglets were infused with Endotoxin (lipopolysaccharide, LPS) for 20 h at 0 (n = 6) and 13 μg/kg•h (n = 8). During the last 2 h, dextrose and an amino acid mixture were infused to attain fed plasma concentrations of amino acids, glucose, and insulin. Fractional protein synthesis rates and translational control mechanisms were examined. LPS reduced protein synthesis in glycolytic muscles by only 13% and had no significant effect in oxidative muscles. This depression was associated with reductions in the phosphorylation of 4E-BP1 (−31%) and S6 K1 (−78%), and a decrease in eIF4G binding to eIF4E (−62%), an event required for formation of the active mRNA binding complex. By comparison, LPS increased protein synthesis in the liver (+29%), spleen (+32%), and kidney (+27%), and in the liver, this increase was associated with augmented eIF4G to eIF4E binding (+88%). In muscle and liver, LPS did not alter eIF2B activity, an event that regulates initiator met-tRNAi binding to the 40S ribosomal complex. These findings suggest that during sustained endotoxemia, the high rate of neonatal muscle protein synthesis is largely maintained in the presence of substrate supply, despite profound changes in translation initiation factors that modulate the mRNA binding step in translation initiation.
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Abbreviations
- LPS:
-
Lipopolysaccharide, endotoxin
- μg:
-
microgram
- Kg:
-
kilogram
- 4E-BP1:
-
eukaryotic initiation factor eIF4E binding protein 1
- eIF4G:
-
eukaryotic initiation factor eIF4G
- eIF4E:
-
eukaryotic initiation factor eIF4E
- S6 K1:
-
ribosomal protein S6 kinase 1
- mRNA:
-
mRNA
- met-tRNAi:
-
initiator methionyl-tRNA
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Acknowledgements
The authors thank William Liu and Susan Nguyen for technical assistance, Frankie Biggs and Jerome Stubblefield for assistance with care of animals, Adam Gillum for graphics assistance, and Leslie Loddeke for editorial assistance, and Linda Weiser for secretarial assistance.
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Supported, in part, by grants from the National Institutes of Health (NIH) AR4447 (T.A.D.), United States Department of Agriculture/Agricultural Research Service 6250-51000-031 (T.A.D.), NIH DK15658 (L.S.J.), NIH DK13499 (L.S.J.) and the NIH training grant T32 HD07445.
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Orellana, R., Kimball, S., Nguyen, H. et al. Regulation of Muscle Protein Synthesis in Neonatal Pigs During Prolonged Endotoxemia. Pediatr Res 55, 442–449 (2004). https://doi.org/10.1203/01.PDR.0000110526.02282.F3
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DOI: https://doi.org/10.1203/01.PDR.0000110526.02282.F3
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