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Sepsis and Mechanical Ventilation Restrain Translation Initiation in Skeletal Muscle by Inducing AMPK‐associated TSC2 Restriction of mTOR Signaling in Pigs
Author(s) -
Orellana Renan,
Srivastava Neeraj,
Suryawan Agus,
Nguyen Hanh,
Almonaci Rose,
Koo Sue Jie,
Gazzaneo Maria C,
Torraza Roberto Murgas,
Davis Teresa,
ElKadi Samer W
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.983.11
Subject(s) - ampk , pi3k/akt/mtor pathway , skeletal muscle , p70 s6 kinase 1 , amp activated protein kinase , phosphorylation , endocrinology , medicine , sepsis , mtorc1 , chemistry , protein kinase a , protein kinase b , signal transduction , biochemistry
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. NIH AR51563, NIH AR44474, and USDA 6250‐51000‐040.