TNFα inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways

Dario Coletti, Ellen Yang, Giovanna Marazzi, David Sassoon

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Cachexia is associated with poor prognosis in patients with chronic disease. Tumor necrosis factor-alpha (TNFα) plays a pivotal role in mediating cachexia and has been demonstrated to inhibit skeletal muscle differentiation in vitro. It has been proposed that TNFαmediated activation of NFκB leads to down regulation of MyoD, however the mechanisms underlying TNFα effects on skeletal muscle remain poorly understood. We report here a novel pathway by which TNFα inhibits muscle differentiation through activation of caspases in the absence of apoptosis. TNFα-mediated caspase activation and block of differentiation are dependent upon the expression of PW1, but occur independently of NFκB activation. PW1 has been implicated previously in p53-mediated cell death and can induce bax translocation to the mitochondria. We show that bax-deficient myoblasts do not activate caspases and differentiate in the presence of TNFα, highlighting a role for bax-dependent caspase activation in mediating TNFα effects. Taken together, our data reveal that TNFα inhibits myogenesis by recruiting components of apoptotic pathways through PW1.

Original languageEnglish
Pages (from-to)631-642
Number of pages12
JournalEMBO Journal
Volume21
Issue number4
DOIs
StatePublished - 15 Feb 2002

Keywords

  • Bax
  • Cachexia
  • Caspase
  • Peg3
  • TNFα

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