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Title: Sepsis and mechnaical ventilation restrain translation initiation in skeletal muscle by inducing AMPK-associated TSC[2] restriction of mTOR signaling in pigs

Author
item Orellana, Renan - Children'S Nutrition Research Center (CNRC)
item Srivastava, Neeraj - Children'S Nutrition Research Center (CNRC)
item Suryawan, Agus - Children'S Nutrition Research Center (CNRC)
item Nguyen, Hanh - Children'S Nutrition Research Center (CNRC)
item Almonaci, Rose - Children'S Nutrition Research Center (CNRC)
item Koo, Sue Jie - Children'S Nutrition Research Center (CNRC)
item Gazzaneo, Maria - Children'S Nutrition Research Center (CNRC)
item Murgas-torrazza, Roberto - Children'S Nutrition Research Center (CNRC)
item Davis, Teresa - Children'S Nutrition Research Center (CNRC)
item El-kadi, Samer - Children'S Nutrition Research Center (CNRC)

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: 1/21/2011
Publication Date: 3/17/2011
Citation: Orellana, R.A., Srivastava, N., Suryawan, A., Nguyen, H.V., Almonaci, R., Koo, S., Gazzaneo, M.C., Murgas-Torrazza, R., Davis, T.A., El-Kadi, S.W. 2011. Sepsis and mechnaical ventilation restrain translation initiation in skeletal muscle by inducing AMPK-associated TSC[2] restriction of mTOR signaling in pigs [abstract]. In: Proceedings of the Federation of American Societies for Experimental Biology Conference, April 07-13, 2011, Washington,D.C. 25:983.11.

Interpretive Summary:

Technical Abstract: In skeletal muscle, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor of AMP: ATP and modulates translation by repressing mammalian target of rapamycin (mTOR) activation. Endotoxin (LPS)-induced sepsis reduces muscle protein synthesis by blunting translation initiation. We hypothesize that mechanical ventilation and sepsis restrain translation in skeletal muscle by activation of AMPK. Neonatal pigs (n=8/group) were subjected to mechanical ventilation for 9 h in the absence (MV) and presence of LPS (LPSMV). AMPK and translation activation signals were determined in longissimus dorsi muscle. Plasma insulin levels rose with MV and were greatest in LPSMV pigs. In muscle, despite higher PKB activation, MV and LPS additively reduced mTOR phosphorylation and decreased the phosphorylation of tuberous sclerosis complex 2 (TSC2) on Thr (1462). AMPK phosphorylation increased during MV and was augmented further in LPSMV pigs. TSC2 phosphorylation on the AMPK site, Ser (1387), increased in MVLPS. MV decreased eIF4G-eIF4E association, which was further decreased by LPS. These findings suggest that both MV and sepsis increase AMPK activation in peripheral skeletal muscle, leading to inhibition of TSC2-mediated mTOR-dependent translation signaling when MV and sepsis coexist.