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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #166090
Title: REGULATION OF MUSCLE PROTEIN SYNTHESIS IN NEONATAL PIGS DURING PROLONGED ENDOTOXEMIA

Author
item ORELLANA, RENAN - BAYLOR COLL OF MEDICINE
item KIMBALL, SCOT - PENN STATE UNIV
item NGUYEN, HANH - BAYLOR COLL OF MEDICINE
item BUSH, JILL - BAYLOR COLL OF MEDICINE
item SURYAWAN, AGUS - BAYLOR COLL OF MEDICINE
item THIVIERGE, CAROLYN - UNIVERSITE LAVAL,CANADA
item JEFFERSON, LEONARD - PENN STATE UNIV
item Davis, Teresa

Submitted to: Pediatric Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/15/2003
Publication Date: 3/1/2004
Citation: Orellana, R.A., Kimball, S.R., Nguyen, H.V., Bush, J.A., Suryawan, A., Thivierge, C., Jefferson, L.S., Davis, T.A. 2004. Regulation of muscle protein synthesis in neonatal pigs during prolonged endotoxemia. Pediatric Research. 55(3):442-449.

Interpretive Summary: Health-care professionals need to know all they can to properly treat individual cases of sepsis, which is a toxic state that nearly always leads to death. Sepsis may differ in important ways between adult and pediatric patients. In a previous study, we induced a septic-like state in newborn pigs, which are models for human infants, by infusing the animals with a dose of E. coli bacteria for 8 hours. We found that their muscle protein synthesis rates declined somewhat, but the decline was nowhere near as severe as the huge drop that occurs under the same conditions in adult humans, rats or swine, based on numbers reported in previous studies. We were curious about the newborn animals' resistance, and especially as to whether the rate might drop further if we infused the toxic dose for a longer time. So we gave newborn pigs a toxic dose that lasted for 20 hours. Then we measured the translation initiation factors which regulate protein synthesis, and we found a huge drop in these factors in the muscle, about as much as that reported in adults under the same circumstances. However, the newborn animals' muscle protein synthesis rates remained high, and did not drop very much beyond the levels we observed in our short-term challenge. The results indicate to us that newborn animals appear to be relatively resistant to the catabolic effects of sepsis as long as they are fed, because they are so sensitive to insulin and amino acids, which rise after eating. It's a far different story in adults, unfortunately, since adults don't get the same degree of protection against sepsis from eating. This information will be extremely helpful to physicians who treat babies at risk of sepsis, and also to researchers who are trying to better understand the protective mechanisms as well as the vulnerabilities babies have against diseases, and, importantly, all these factors work in the presence or absence of good nutrition.

Technical 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 microg/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-tRNA(i) 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.