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TNFα inhibits skeletal myogenesis through a PW1‐dependent pathway by recruitment of caspase pathways
Author(s) -
Coletti Dario,
Yang Ellen,
Marazzi Giovanna,
Sassoon David
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.4.631
Subject(s) - biology , myogenesis , microbiology and biotechnology , caspase 8 , tumor necrosis factor alpha , caspase 2 , caspase , apoptosis , genetics , myocyte , immunology , programmed cell death
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 TNFα‐mediated 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.