Issn Print: 0277-2116

Publication Date: 2004/06/01


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P0585 ROTAVIRUS ENTERITIS OF MALNOURISHED PIGS INCREASES INTESTINAL ACTIVITY OF RIBOSOMAL P70 S6 KINASE, INCREASES GUT PROTEIN SYNTHESIS AND REDUCES MUSCLE PROTEIN SYNTHESIS

M. Rhoads; R. Harrell; O. Phillips; L. Gatlin; B. Corl; Q. Fu; J. Odle

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Author Information: Pediatrics, Ochsner Clinic Foundation, New Orleans, LA,

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Introduction: The rate of protein synthesis in eukaryotic cells is controlled by the mammalian target of rapamycin (mTOR/FRAP). mTOR regulates the activity of ribosomal protein s6 kinase (p70s6k) and ribosomal protein 4E-BP1. mTOR activity has been called the “amino acid sensor” of eukaryotic cells. Because intestinal cell migration after wounding is markedly reduced by cycloheximide and rapamycin, we postulated that protracted diarrhea of infancy in malnourished hosts is mediated by downregulation of mTOR/p70s6k.
Methods: Eight non-infected control pigs received full-strength formula. Eight infected pigs received a 50% restriction of formula, which we have previously shown results in “protracted diarrhea of infancy.” Infection was initiated by inoculation with porcine rotavirus on day 6 of life. We compared rates of ex vivo ileal and semitendonosus muscle 3H-phenylalanine incorporation into protein, and we quantified phosphorylation of p70s6k (by western blot)(probed with antibody to phospho-Thr421/Ser424) on days 0, 1, 3, 5,and 11 post-infection (p.i.).
Results: Because feeding markedly activated p70s6k in pig ileum (n=3 additional pigs), all subjects were studied after a 9-h fast. At each time-point p.i., intestinal protein synthetic rate in infected pigs was increased 30–50%, while muscle protein synthesis decreased 30–50% compared with control pigs. Peaking on days 3 and 5 post-infection, the activation level of p70s6k was increased >4-fold in intestinal tissue. The p85 isoform (nuclear p70s6k) was activated significantly more than the p70 isoform (cytoplasmic) by infection, with a peak activation on day 3.
Conclusion: Our results support dynamic control of intestinal protein synthesis and p70s6k by feeding. Furthermore, infectious enteritis results in increased bowel protein synthesis, in parallel to significant activation of p70s6k, while muscle protein synthesis is coordinately reduced. The increase in intestinal protein synthesis and p70s6k activity occurs in an epithelium enriched with metabolically active, proliferating crypt cells.
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