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Effects of oxidative stress on PI3K/Akt regulation of FOXO transcription factors during diaphragm muscle disuse
Author(s) -
McClung Joseph M.,
Kavazis Andreas N.,
DeRuisseau Keith C.,
Falk Darin J.,
Whidden Melissa A.,
Powers Scott K.
Publication year - 2007
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.21.6.a1306-c
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , foxo1 , oxidative stress , trolox , foxo3 , phosphoinositide 3 kinase , microbiology and biotechnology , phosphorylation , chemistry , keap1 , kinase , signal transduction , transcription factor , biology , biochemistry , gene , antioxidant capacity
Oxidative stress is a key component of mechanical ventilation (MV)‐induced diaphragm disuse atrophy. We hypothesized that MV‐induced oxidative stress down‐regulates phosphotidylinositol 3‐kinase/Akt serine/threonine kinase (PI3K/Akt) signaling and activates the forkhead box O (FOXO) class of transcription factors. Sprague‐Dawley rats were assigned to control, 6‐ or 18‐hour MV with or without administration of the antioxidant, Trolox. 6‐hour MV decreased PI3K/Akt activation, induced FOXO1 nuclear localization and transcriptional activity, and increased gene expression of the ubiquitin ligases MAFbx and MuRF‐1, independent of Trolox. 18‐hour MV activated PI3K, stimulated nuclear localization of Akt, and induced mammalian target of rapamycin (mTOR) activity, but failed to stimulate further signaling responsible for protein synthesis initiation. Surprisingly, prevention of MV induced oxidative stress by Trolox attenuated phosphoinositide‐dependent kinase‐1 (PDK1) phosphorylation and induced p70s6kinase, but did not alter the 18‐hour MV induction of PI3K/Akt, FOXO1 transcriptional activity, or MAFbx /MuRF‐1 gene expression. Collectively, these data suggest differential regulation of PI3K/Akt/FOXO signaling during the early and late stages of MV diaphragm disuse and only limited sensitivity of this pathway to oxidative stress. Supported by NIH (R01 HL072789) awarded to S.K. Powers.