期刊
FASEB JOURNAL
卷 19, 期 3, 页码 362-370出版社
WILEY
DOI: 10.1096/fj.04-2364com
关键词
tumor necrosis factor; muscle wasting; ubituitin conjugating activity
资金
- NHLBI NIH HHS [HL59878, R01 HL061543, R01 HL058081, HL42250-10/10, R01 HL059878, HL58081, R01 HL042250] Funding Source: Medline
- NIAMS NIH HHS [R01 AR049022-02, R01 AR049022, AR049022] Funding Source: Medline
- NIGMS NIH HHS [GM59203] Funding Source: Medline
Atrogin1/MAFbx is an ubiquitin ligase that mediates muscle atrophy in a variety of catabolic states. We recently found that H2O2 stimulates atrogin1/MAFbx gene expression. Since the cytokine tumor necrosis factor-alpha (TNF-alpha) stimulates both reactive oxygen production and general activity of the ubiquitin conjugating pathway, we hypothesized that TNF-alpha would also increase atrogin1/MAFbx gene expression. As with H2O2, we found that TNF-alpha exposure upregulates atrogin1/MAF-bx mRNA within 2 h in C2C12 myotubes. Intraperitoneal injection of TNF-alpha increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF-alpha or H2O2 also produced general activation of the mitogen-activated protein kinases (MAPKs): p38, ERK1/2, and JNK. The increase in atrogin1/MAFbx gene expression induced by TNF-alpha was not altered significantly by ERK inhibitor PD98059 or the JNK inhibitor SP600125. In contrast, atrogin1/MAFbx up-regulation and the associated increase in ubiquitin conjugating activity were both blunted by p38 inhibitors, either SB203580 or curcumin. These data suggest that TNF-alpha acts via p38 to increase atrogin1/MAFbx gene expression in skeletal muscle.
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