AMP-activated protein kinase enhances the expression of muscle-specific ubiquitin ligases despite its activation of IGF-1/Akt signaling in C2C12 myotubes

Autor: Min Du, Xu Yan, Mei J. Zhu, Jun F. Tong
Rok vydání: 2009
Předmět:
Muscle Fibers
Skeletal
Muscle Proteins
Cell Cycle Proteins
AMP-Activated Protein Kinases
Biochemistry
Tripartite Motif Proteins
Mice
AMP-activated protein kinase
Phosphoprotein Phosphatases
Eukaryotic Initiation Factors
Insulin-Like Growth Factor I
Phosphorylation
biology
TOR Serine-Threonine Kinases
Forkhead Box Protein O3
Cell Differentiation
Forkhead Transcription Factors
Ubiquitin ligase
Cell biology
Protein Transport
FOXO3
Signal transduction
Signal Transduction
medicine.medical_specialty
Ubiquitin-Protein Ligases
Gene Expression Regulation
Enzymologic
Cell Line
Internal medicine
medicine
Animals
Muscle
Skeletal
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Adaptor Proteins
Signal Transducing
Sirolimus
SKP Cullin F-Box Protein Ligases
Dose-Response Relationship
Drug
AMPK
Cell Biology
Aminoimidazole Carboxamide
Phosphoproteins
Adenosine Monophosphate
Endocrinology
biology.protein
Ribonucleosides
Carrier Proteins
Protein Kinases
Proto-Oncogene Proteins c-akt
Acetyl-CoA Carboxylase
Zdroj: Journal of Cellular Biochemistry. 108:458-468
ISSN: 1097-4644
0730-2312
DOI: 10.1002/jcb.22272
Popis: 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.
Databáze: OpenAIRE
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