TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways.
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.
Coletti
Dario
D
Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, USA.
Yang
Ellen
E
Marazzi
Giovanna
G
Sassoon
David
D
D000818:Animals; D001483:Base Sequence; D002100:Cachexia / Q000378:metabolism / Q000503:physiopathology*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D015342:DNA Probes; D004789:Enzyme Activation; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology* / Q000201:enzymology / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D015342:DNA Probes; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D020169:Caspases