Mitochondria Mediate Tumor Necrosis Factor-α/NF-κB Signaling in Skeletal Muscle Myotubes

Abstract

Tumor necrosis factor-α (TNF-α) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-α directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor κB (NF-κB). We also have found that protein loss induced by TNF-α is NF-κB dependent. In the present study, we analyzed the signaling pathway by which TNF-α activates NF-κB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-κB by TNF-α was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-α activation of NK-κB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-κB activation in muscle. In addition, we found that TNF-α stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca²⁺, phospholipase A2 (PLA₂), and nitric oxide (NO) do not appear to be involved in the activation of NF-κB.