View the Current Issue

Article

  • The EMBO Journal (2002) 21, 631 - 642
  • doi:10.1093/emboj/21.4.631

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

Dario Coletti1,2, Ellen Yang1,2, Giovanna Marazzi1 and David Sassoon1

  1. Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, USA
  2. D.Coletti and E.Yang contributed equally to this work

Correspondence to:

David Sassoon, E-mail: david.sassoon@mssm.edu

Received 7 June 2001; Accepted 19 December 2001; Revised 23 November 2001

Cachexia is associated with poor prognosis in patients with chronic disease. Tumor necrosis factor-alpha (TNFalpha) plays a pivotal role in mediating cachexia and has been demonstrated to inhibit skeletal muscle differentiation in vitro. It has been proposed that TNFalpha-mediated activation of NFkappaB leads to down regulation of MyoD, however the mechanisms underlying TNFalpha effects on skeletal muscle remain poorly understood. We report here a novel pathway by which TNFalpha inhibits muscle differentiation through activation of caspases in the absence of apoptosis. TNFalpha-mediated caspase activation and block of differentiation are dependent upon the expression of PW1, but occur independently of NFkappaB 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 TNFalpha, highlighting a role for bax-dependent caspase activation in mediating TNFalpha effects. Taken together, our data reveal that TNFalpha inhibits myogenesis by recruiting components of apoptotic pathways through PW1.

  • Keywords:

    • bax,
    • cachexia,
    • caspase,
    • Peg3,
    • TNFalpha