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TNF induces atrogin‐1 expression via AKT‐independent activation of Foxo4
Author(s) -
Moylan Jennifer Stevenson,
Smith Jeffrey D,
Smith Melissa A,
McLoughlin Thomas J,
Reid Michael B
Publication year - 2008
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.22.1_supplement.962.30
Subject(s) - foxo1 , protein kinase b , myogenesis , tumor necrosis factor alpha , pi3k/akt/mtor pathway , chemistry , medicine , phosphorylation , endocrinology , c2c12 , biology , microbiology and biotechnology , signal transduction , skeletal muscle
Atrophy of murine skeletal muscle during starvation is regulated by atrogin‐1, a muscle‐specific ubiquitin ligase. Starvation decreases AKT activity which removes inhibition of the forkhead transcription factors Foxo1 and 3a and thereby stimulates atrogin‐1 gene expression. Atrogin‐1 is also regulated by tumor necrosis factor (TNF). We tested the hypothesis that TNF increases atrogin‐1 via AKT and Foxo1/3a. Data from C2C12 myotubes indicate that the AKT/Foxo1/atrogin‐1 pathway is intact in these cells. Wortmannin inhibits AKT phosphorylation, increasing atrogin‐1 mRNA. Overexpression of Foxo1 also increases atrogin‐1 mRNA. Paradoxically, TNF increases phospho‐AKT as it increases atrogin‐1 mRNA. Even in the presence of insulin‐like growth factor stimulated AKT, TNF retains the ability to increase atrogin‐1. In addition, TNF is unable to induce nuclear translocation of Foxo1/3a. Instead, TNF increases protein levels and stimulates nuclear translocation of Foxo4, an alternate Foxo isoform. This isoform appears to promote TNF‐induced atrogin‐1 expression since Foxo4 siRNA partially inhibits the TNF effects. In conclusion, we propose that TNF activates atrogin‐1 expression independent of AKT via Foxo4. These results suggest a mechanism by which inflammatory catabolic states persist in the presence of adequate growth factors and nutrition. Supported by NIH grant HL59878 (MBR).