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 (> or = 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
Bin
B
Renal Division, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ohkawa
Sakae
S
Li
Haiyan
H
Roberts-Wilson
Tiffany K
TK
Price
S Russ
SR
D000818:Animals; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D018485:Muscle Fibers, Skeletal; D009124:Muscle Proteins / Q000235:genetics*; D009133:Muscular Atrophy / Q000139:chemically induced*; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D015398:Signal Transduction; D025801:Ubiquitin / Q000235:genetics*
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D005938:Glucocorticoids; D009124:Muscle Proteins; D025801:Ubiquitin; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases