NF-κB-induced loss of MyoD mRNA may play a role in muscle decay and cachexia. MyoD regulates skeletal muscle differentiation (SMD) and is essential for tissue repair. NF-κB, activated by TNF, inhibits SMD by suppressing MyoD mRNA at the posttranscriptional level. In differentiating C2C12 myocytes, TNF activates NF-κB, which suppresses MyoD mRNA. In contrast, in differentiated myotubes, TNF plus IFN-γ signaling is required for NF-κB-dependent down-regulation of MyoD and dysfunction of skeletal myofibers. MyoD mRNA is also downregulated by TNF and IFN-γ in mouse muscle in vivo. These findings suggest a possible mechanism underlying skeletal muscle decay in cachexia. Skeletal muscle differentiation is controlled by myogenic bHLH transcription factors (MyoD, Myf5, myogenin, MRF4) and MEF2A-D. MyoD and Myf5 are expressed in proliferating myoblasts and are activated to initiate SMD. MyoD-deficient skeletal muscle is impaired in regeneration. NF-κB inhibits SMD by regulating cyclin D1. TNF activates NF-κB, causing it to translocate to the nucleus and bind to inflammatory and proliferative gene promoters. TNF is a mediator of skeletal muscle wasting in cachexia, a syndrome characterized by weight loss and wasting. Cachexia is common in chronic diseases like cancer and AIDS. Little is known about its molecular etiology, and few targets have been identified for therapy. Here, the potential role of NF-κB as a downstream effector of TNF-mediated skeletal muscle dysfunction is investigated. TNF inhibits skeletal myogenesis in vitro. NF-κB is a downstream TNF effector that regulates MyoD expression. Reporter assays in mouse 10T1/2 fibroblasts showed that p65 subunit of NF-κB suppresses MyoD expression. p65 alone was sufficient to reduce MyoD protein levels. p65 also reduced MyoD mRNA levels. These results indicate that TNF regulation of MyoD in C2C12 cells is dependent on NF-κB activity and that p65 is sufficient to induce down-regulation of MyoD mRNA. TNF is a key mediator in skeletal muscle degeneration associated with cancer-induced cachexia. Direct inhibition of NF-κB blocks cachexia in an animal model, suggesting a link between NF-κB and TNF in this disease. TNF alone induces weight loss in animals, but in vitro studies show that TNF does not induce muscle degeneration. This suggests that another factor is required. In contrast, differentiated myotubes are refractory to TNF withNF-κB-induced loss of MyoD mRNA may play a role in muscle decay and cachexia. MyoD regulates skeletal muscle differentiation (SMD) and is essential for tissue repair. NF-κB, activated by TNF, inhibits SMD by suppressing MyoD mRNA at the posttranscriptional level. In differentiating C2C12 myocytes, TNF activates NF-κB, which suppresses MyoD mRNA. In contrast, in differentiated myotubes, TNF plus IFN-γ signaling is required for NF-κB-dependent down-regulation of MyoD and dysfunction of skeletal myofibers. MyoD mRNA is also downregulated by TNF and IFN-γ in mouse muscle in vivo. These findings suggest a possible mechanism underlying skeletal muscle decay in cachexia. Skeletal muscle differentiation is controlled by myogenic bHLH transcription factors (MyoD, Myf5, myogenin, MRF4) and MEF2A-D. MyoD and Myf5 are expressed in proliferating myoblasts and are activated to initiate SMD. MyoD-deficient skeletal muscle is impaired in regeneration. NF-κB inhibits SMD by regulating cyclin D1. TNF activates NF-κB, causing it to translocate to the nucleus and bind to inflammatory and proliferative gene promoters. TNF is a mediator of skeletal muscle wasting in cachexia, a syndrome characterized by weight loss and wasting. Cachexia is common in chronic diseases like cancer and AIDS. Little is known about its molecular etiology, and few targets have been identified for therapy. Here, the potential role of NF-κB as a downstream effector of TNF-mediated skeletal muscle dysfunction is investigated. TNF inhibits skeletal myogenesis in vitro. NF-κB is a downstream TNF effector that regulates MyoD expression. Reporter assays in mouse 10T1/2 fibroblasts showed that p65 subunit of NF-κB suppresses MyoD expression. p65 alone was sufficient to reduce MyoD protein levels. p65 also reduced MyoD mRNA levels. These results indicate that TNF regulation of MyoD in C2C12 cells is dependent on NF-κB activity and that p65 is sufficient to induce down-regulation of MyoD mRNA. TNF is a key mediator in skeletal muscle degeneration associated with cancer-induced cachexia. Direct inhibition of NF-κB blocks cachexia in an animal model, suggesting a link between NF-κB and TNF in this disease. TNF alone induces weight loss in animals, but in vitro studies show that TNF does not induce muscle degeneration. This suggests that another factor is required. In contrast, differentiated myotubes are refractory to TNF with