FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin‐1/MAFbx expression during glucocorticoid‐induced skeletal muscle atrophy

Muscle atrophy is a consequence of chronic diseases ( e.g ., diabetes) and glucocorticoid‐induced insulin resistance that results from enhanced activity of the ubiquitin‐proteasome pathway. The PI3K/Akt pathway inhibits the FOXO‐mediated transcription of the muscle‐specific E3 ligase atrogin‐1/MAFbx (AT‐1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (UbC) expression. The observations raise a question about how the transcription of these atrogenes is synchronized in atrophic muscle. We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT‐1 and UbC expression. In rat L6 myotubes, dexamethasone (≥24 h) reduced insulin receptor substrate (IRS)‐1 protein and PI3K/Akt signaling and increased AT‐1 mRNA. IRS‐2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. Knockdown of IRS‐1 using small interfering RNA or adenovirus‐mediated expression of constitutively activated FOXO3a increased IRS‐2 protein, MEK/ERK signaling, and UbC expression. Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin‐induced insulin deficiency and concurrently elevated glucocorticoid production. IRS‐1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS‐2, UbC and AT‐1 were increased. We conclude that FOXO3a mediates a reciprocal communication between the IRS‐1/PI3K/Akt and IRS‐2/MEK/ERK pathways that coordinates AT‐1 and ubiquitin expression during muscle atrophy.—Zheng, B., Ohkawa, S., Li, H., Roberts‐Wilson, T.‐K., Price, S. R. FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin‐1/MAFbx expression during glucocorticoid‐induced skeletal muscle atrophy. FASEB J . 24, 2660–2669 (2010). www.fasebj.org