Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2006
Publication Date: 10/17/2006
Citation: Orellana, R.A., Kimball, S.R., Suryawan, A., Escobar, J., Nguyen, H.V., Jefferson, L.S., Davis, T.A. 2007. Insulin stimulates muscle protein synthesis in neonates during endotoxemia despite repression of translation initiation. American Journal of Physiology Endocrinology and Metabolism. 292(2):E629-E636. Interpretive Summary: Infection reduces protein synthesis in the muscle of neonates. To examine the role of insulin in this response, we infused neonatal pigs with a bacterial toxin, and provided insulin treatment. In this study, we manipulated hormones and nutrients to allow stimulation of protein synthesis in muscle by insulin in neonatal pigs. We found that the bacterial toxin reduced muscle protein synthesis, but when we provided insulin treatment we improved protein synthesis in the muscle of the sick neonatal pig as much as in the normal piglet. We also found cellular changes that explained the possible molecular mechanism. This research may help in designing insulin therapy in acutely ill neonates to maintain their nutritional state.
Technical Abstract: 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.