Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α

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Abstract
Skeletal muscle atrophy and weakness are thought to be stimulated by tumor necrosis factor α (TNF-α) in a variety of chronic diseases. However, little is known about the direct effects of TNF-α on differentiated skeletal muscle cells or the signaling mechanisms involved. We have tested the effects of TNF-α on the mouse-derived C2C12 muscle cell line and on primary cultures from rat skeletal muscle. TNF-α treatment of differentiated myotubes stimulated time- and concentration-dependent reductions in total protein content and loss of adult myosin heavy chain (MHCf) content; these changes were evident at low TNF-α concentrations (1–3 ng/ml) that did not alter muscle DNA content and were not associated with a decrease in MHCf synthesis. TNF-α activated binding of nuclear factor κB (NF-κB) to its targeted DNA sequence and stimulated degradation of I-κBα, an NF-κB inhibitory protein. TNF-α stimulated total ubiquitin conjugation whereas a 26S proteasome inhibitor (MG132 10–40 μM) blocked TNF-α activation of NF-κ...