TY - JOUR
T1 - Tumor necrosis factor-alpha inhibits myogenic differentiation through MyoD protein destabilization
AU - Langen, R.C.
AU - van der Velden, A.L.J.
AU - Schols, A.M.
AU - Kelders, M.C.J.M.
AU - Wouters, E.F.
AU - Janssen-Heininger, Y.M.W.
PY - 2004/1/1
Y1 - 2004/1/1
N2 - Tumor necrosis factor alpha (TNFalpha) has been implicated as a mediator of muscle wasting through nuclear factor kappa B (NF-kappaB) -dependent inhibition of myogenic differentiation. The aim of the present study was to identify the regulatory molecule(s) of myogenesis targeted by TNFalpha/NF-kappaB signaling. TNFalpha interfered with cell cycle exit and repressed the accumulation of transcripts encoding muscle-specific genes in differentiating C2C12 myoblasts. Overexpression of a p65 (RelA) mutant lacking the transcriptional activation domain attenuated the TNFalpha-mediated inhibition of muscle-specific gene transcription. The ability of muscle regulatory factor MyoD to induce muscle-specific transcription in 10T1/2 fibroblasts was also disrupted by wild-type p65, demonstrating that NF-kappaB transcriptional activity interferes with the function of MyoD. Inhibition of muscle-specific gene expression by TNFalpha was restored by overexpression of MyoD, whereas endogenous MyoD protein abundance and stability were reduced by TNFalpha through increased proteolysis of MyoD by the ubiquitin proteasome pathway. Last, the inhibitory effects of TNFalpha on myogenic differentiation were demonstrated in a mouse model of skeletal muscle regeneration, in which TNFalpha caused a delay in myoblast cell cycle exit. These results implicate that TNFalpha inhibits myogenic differentiation through destabilizing MyoD protein in a NF-kappaB-dependent manner, which interferes with skeletal muscle regeneration and may contribute to muscle wasting.
AB - Tumor necrosis factor alpha (TNFalpha) has been implicated as a mediator of muscle wasting through nuclear factor kappa B (NF-kappaB) -dependent inhibition of myogenic differentiation. The aim of the present study was to identify the regulatory molecule(s) of myogenesis targeted by TNFalpha/NF-kappaB signaling. TNFalpha interfered with cell cycle exit and repressed the accumulation of transcripts encoding muscle-specific genes in differentiating C2C12 myoblasts. Overexpression of a p65 (RelA) mutant lacking the transcriptional activation domain attenuated the TNFalpha-mediated inhibition of muscle-specific gene transcription. The ability of muscle regulatory factor MyoD to induce muscle-specific transcription in 10T1/2 fibroblasts was also disrupted by wild-type p65, demonstrating that NF-kappaB transcriptional activity interferes with the function of MyoD. Inhibition of muscle-specific gene expression by TNFalpha was restored by overexpression of MyoD, whereas endogenous MyoD protein abundance and stability were reduced by TNFalpha through increased proteolysis of MyoD by the ubiquitin proteasome pathway. Last, the inhibitory effects of TNFalpha on myogenic differentiation were demonstrated in a mouse model of skeletal muscle regeneration, in which TNFalpha caused a delay in myoblast cell cycle exit. These results implicate that TNFalpha inhibits myogenic differentiation through destabilizing MyoD protein in a NF-kappaB-dependent manner, which interferes with skeletal muscle regeneration and may contribute to muscle wasting.
U2 - 10.1096/fj.03-0251com
DO - 10.1096/fj.03-0251com
M3 - Article
C2 - 14769817
SN - 0892-6638
VL - 18
SP - 227
EP - 237
JO - Faseb Journal
JF - Faseb Journal
IS - 2
ER -