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Tong, JF, Yan, X, Zhu, MJ and Du, M (2009) AMP-activated protein kinase enhances the expression of muscle-specific ubiquitin ligases despite its activation of IGF-1/Akt signaling in C2C12 myotubes. J. Cell. Biochem. 108:458-68
Two muscle-specific ubiquitin ligases (UL), muscle atrophy F box (MAFbx) and muscle RING finger 1 (MuRF1), are crucial for myofibrillar protein breakdown. The insulin like growth factor-1 (IGF-1) pathway inhibits muscle UL expression through Akt-mediated inhibition of FoxO transcription factors, while AMP-activated protein kinase (AMPK) promotes UL expression. The underlying cellular mechanism, however, remains obscure. In this study, the effect of AMPK and its interaction with IGF-1 on ubiquitin ligases expression was investigated. C2C12 myotubes were treated with 0, 0.1, 0.3, and 1.0 mM 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) in the presence or absence of 50 ng/ml IGF-1. IGF-1 activated Akt, which enhanced phosphorlytion of FoxO3a at Thr 318/321 and reduced the expression of UL. Intriguingly, though activation of AMPK by 0.3 and 1.0 mM AICAR synergized IGF-1-induced Akt activation, the expression of UL was not attenuated, but strengthened by AMPK activation. AICAR treatment decreased FoxO3a phosphorylation at 318/321 in the cytoplasm and induced FoxO3 nuclear relocation. mTOR inhibition increased basal MAFbx expression and reversed the inhibitory effect of IGF-1 on UL expression. In conclusion, our data show that AMPK activation by AICAR stimulates UL expression despite the activation of Akt signaling, which may be due to the possible antagonistic effect of FoxO phosphorylation by AMPK on phosphorylation by Akt. In addition, AMPK inhibition of mTOR may provide an additional explanation for the enhancement of UL expression by AMPK.
AMP-Activated Protein Kinases/antagonists & inhibitors; AMP-Activated Protein Kinases/metabolism; Acetyl-CoA Carboxylase/metabolism; Adenosine Monophosphate/agonists; Aminoimidazole Carboxamide/analogs & derivatives; Aminoimidazole Carboxamide/pharmacology; Animals; Carrier Proteins/metabolism; Cell Differentiation; Cell Line; Dose-Response Relationship, Drug; Forkhead Transcription Factors/metabolism; Gene Expression Regulation, Enzymologic; Insulin-Like Growth Factor I/metabolism; Insulin-Like Growth Factor I/pharmacology; Mice; Muscle Fibers, Skeletal/cytology; Muscle Fibers, Skeletal/drug effects; Muscle Fibers, Skeletal/enzymology; Muscle Proteins/genetics; Muscle Proteins/metabolism; Muscle, Skeletal/enzymology; Phosphoprotein Phosphatases/antagonists & inhibitors; Phosphoproteins/metabolism; Phosphorylation/drug effects; Protein Kinases/metabolism; Protein Transport/drug effects; Proto-Oncogene Proteins c-akt/metabolism; Ribonucleosides/pharmacology; SKP Cullin F-Box Protein Ligases/genetics; SKP Cullin F-Box Protein Ligases/metabolism; Signal Transduction; Sirolimus/pharmacology; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism
|Gene product||Qualifier||GO Term||Evidence Code||with/from||Aspect||Extension||Notes||Status|
|GO:0004679: regulation of gene expression, epigenetic||
Refer to figure 6B on phosphorylation levels
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