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Title: ENDOTOXIN INDUCES DIFFERENTIAL REGULATION OF MTOR-DEPENDENT SIGNALING IN SKELETAL MUSCLE AND LIVER OF NEONATAL PIGS

Author
item KIMBALL, SCOT - PENN STATE UNIV COL MED
item ORELLANA, RENAN - BAYLOR COLLEGE MED
item O'CONNOR, PAMELA - BAYLOR COLLEGE MED
item SURYAWAN, AGUS - BAYLOR COLLEGE MED
item BUSH, JILL - BAYLOR COLLEGE MED
item NGUYEN, HANH - BAYLOR COLLEGE MED
item THIVIERGE, CAROLE - UNIV LAVAL ST-FOY QUEBEC
item JEFFERSON, LEONARD - PENN STATE UNIV COL MED
item Davis, Teresa

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/16/2003
Publication Date: 5/28/2003
Citation: Kimball, S.R., Orellana, R.A., O'Connor, P.M.J., Suryawa, A., Bush, J.A., Nguyen, H.V., Thivierge, M.C., Jefferson, L.S., Davis, T.A. Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs. American Journal of Physiology Endocrinology and Metabolism. 285:E637-E644.

Interpretive Summary: Sepsis is an acute inflammatory state that can lead to death. We used newborn piglets as models of human babies to determine whether babies with sepsis synthesize less muscle protein than healthy babies. This is important because a reduced rate of muscle protein synthesis would lead to muscle wasting. This frequently occurs in adults with sepsis. We also wished to identify the mechanisms that are responsible for regulating the synthesis of muscle proteins during sepsis. The results suggest that if newborns are fed when they are septic, that the synthesis of their muscle proteins is reduced only about 15%. Thus, newborns appear to be relatively resistant to the catabolic effects of sepsis, unlike adults. We also identified intracellular signaling molecules that are altered in the muscles of newborns with sepsis and some that function normally during sepsis. This information will be helpful to physicians who treat babies with sepsis and to researchers who are trying to understand how muscle mass is regulated.

Technical Abstract: In the present study, differential responses of regulatory proteins involved in translation initiation in skeletal muscle and liver during sepsis were studied in neonatal pigs treated with lipopolysaccharide (LPS). LPS did not alter eukaryotic initiation factor (eIF) 2B activity in either tissue. In contrast, binding of eIF4G to eIF4E to form the active mRNA-binding complex was repressed in muscle and enhanced in liver. Phosphorylation of eIF4E-binding protein, 4E-BP1, and ribosomal protein S6 kinase, S6K1, was reduced in muscle during sepsis but increased in liver. Finally, changes in 4E-BP1 and S6K1 phosphorylation were associated with altered phosphorylation of the protein kinase mammalian target of rapamycin (mTOR). Overall, the results suggest that translation initiation in both skeletal muscle and liver is altered during neonatal sepsis by modulation of the mRNA-binding step through changes in mTOR activation. Moreover, the LPS-induced changes in factors that regulate translation initiation are more profound than previously reported changes in global rates of protein synthesis in the neonate. This finding suggests that the initiator methionyl-tRNA-rather than the mRNA-binding step in translation initiation may play a more critical role in maintaining protein synthesis rates in the neonate during sepsis.