TNF-α acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle

Yi Ping Li, Yuling Chen, Joseph John, Jennifer Moylan, Bingwen Jin, Douglas L. Mann, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

481 Scopus citations


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-α (TNF-α) stimulates both reactive oxygen production and general activity of die ubiquitin conjugating pathway, we hypothesized that TNF-α would also increase atrogin1/MAFbx gene expression. As with H 2O2, we found that TNF-α exposure upregulates atrogin1/MAFbx mRNA within 2 h in C2C12 myotubes. Intraperitoneal injection of TNF-α increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF-α or H2O 2 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-α was not altered significantly by ERK inhibitor PD98059 or the JNK inhibitor SP600125. In contrast, atrogin1/MAFbx up-regulation and die associated increase in ubiquitin conjugating activity were both blunted by p38 inhibitors, either SB203580 or curcumin. These data suggest that TNF-α acts via p38 to increase atrogin1/MAFbx gene expression in skeletal muscle.

Original languageEnglish
Pages (from-to)362-370
Number of pages9
JournalFASEB Journal
Issue number3
StatePublished - Mar 2005


  • Muscle wasting
  • Tumor necrosis factor
  • Ubituitin conjugating activity

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics


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