Résumé
Abstract only Serum tumor necrosis factor–alpha (TNF) is elevated in chronic inflammatory diseases that cause muscle weakness including chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cancer. Beyond stimulating atrophy, TNF can act directly on muscle fibers to increase cytosolic oxidant activity which depresses specific force, evidence of contractile dysfunction. Our current study evaluated the roles of specific oxidant cascades ‐‐ reactive oxygen species (ROS) and nitric oxide (NO) derivatives ‐‐ as mediators of TNF‐induced dysfunction. We tested the hypothesis that muscle‐derived ROS and NO both contribute to TNF‐induced dysfunction. Mouse diaphragm fiber bundles were studied in vitro . We found that TNF exposure stimulated a 25% increase in overall oxidant activity (P<0.05; DCF oxidation assay) and depressed specific force at stimulus frequencies of 1–300 Hz (P<0.05). Both effects were diminished by pretreatment with either superoxide dismutase (SOD; degrades superoxide anion) or catalase (degrades H 2 0 2 ), confirming ROS involvement. TNF exposure also stimulated a 39% increase in NO activity (P<0.05; DAF assay) that was abolished by pretreatment with N (omega)‐nitro‐l‐arginine methyl ester (L‐NAME; inhibits NO synthase). L‐NAME pretreatment or genetic deficiency of neuronal NO synthase (nNOS) preserved specific force of TNF‐treated muscle (P<0.05). We conclude that muscle‐derived ROS and NO are both required for TNF‐induced dysfunction and speculate that peroxynitrite may be a common downstream mediator of TNF action. Supported by NIH grants HL08341 (fellowship to SAS) and AR055974 (MBR).