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Insulin stimulates muscle protein synthesis in neonates during endotoxemia despite repression of translation initiation

¹United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center and Critical Care Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and ²Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Submitted 4 May 2006 ; accepted in final form 12 October 2006

Skeletal muscle protein synthesis is reduced in neonatal pigs in response to endotoxemia. To examine the role of insulin in this response, neonatal pigs were infused with endotoxin (LPS, 0 and 10 µg·kg^–1·h^–1), whereas glucose and amino acids were maintained at fasting levels and insulin was clamped at fasting or fed (2 or 10 µU/ml) levels. Fractional rates of protein synthesis and translational control mechanisms were examined in longissimus dorsi muscle and liver. In the presence of fasting insulin, LPS reduced muscle protein synthesis (–29%), and increasing insulin to fed levels accelerated muscle protein synthesis in both groups (controls, +44%; LPS, +64%). LPS, but not insulin, increased liver protein synthesis by +28%. In muscle of fasting neonatal pigs, LPS reduced 4E-BP1 phosphorylation and eIF4E to eIF4G binding. In muscle of controls, but not LPS pigs, raising insulin to fed levels increased 4E-BP1 and S6K1 phosphorylation and eIF4E to eIF4G binding. In muscle and liver, neither LPS nor insulin altered eIF2B activity. eEF2 phosphorylation decreased in response to insulin in both LPS and control animals. The results suggest that, in endotoxemic neonatal animals, the response of protein synthesis to insulin is maintained despite suppression of mTOR-dependent translation initiation and eIF4E availability for eIF4F assembly. Maintenance of an anabolic response to the feeding-induced rise in insulin likely exerts a protective effect for the neonate to the catabolic processes induced by sepsis.

eukaryotic elongation factor 2; sepsis; mammalian target of rapamycin; eukaryotic initiation factors 4G and 4E

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