title: TNF signals via neuronal-type nitric oxide synthase and reactive oxygen species to depress specific force of skeletal muscle.
abstract: TNF promotes skeletal muscle weakness, in part, by depressing specific force of muscle fibers. This is a rapid, receptor-mediated response, in which TNF stimulates cellular oxidant production, causing myofilament dysfunction. The oxidants appear to include nitric oxide (NO); otherwise, the redox mechanisms that underlie this response remain undefined. The current study tested the hypotheses that 1) TNF signals via neuronal-type NO synthase (nNOS) to depress specific force, and 2) muscle-derived reactive oxygen species (ROS) are essential co-mediators of this response. Mouse diaphragm fiber bundles were studied using live cell assays. TNF exposure increased general oxidant activity (P < 0.05; 2',7'-dichlorodihydrofluorescein diacetate assay) and NO activity (P < 0.05; 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate assay) and depressed specific force across the full range of stimulus frequencies (1-300 Hz; P < 0.05). These responses were abolished by pretreatment with N(ω)-nitro-L-arginine methyl ester (L-NAME; a nonspecific inhibitor of NOS activity), confirming NO involvement. Genetic nNOS deficiency replicated L-NAME effects on TNF-treated muscle, diminishing NO activity (-80%; P < 0.05) and preventing the decrement in specific force (P < 0.05). Comparable protection was achieved by selective depletion of muscle-derived ROS. Pretreatment with either SOD (degrades superoxide anion) or catalase (degrades hydrogen peroxide) depressed oxidant activity in TNF-treated muscle and abolished the decrement in specific force. These findings indicate that TNF signals via nNOS to depress contractile function, a response that requires ROS and NO as obligate co-mediators.
authors.affiliation: Department of Physiology and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky 40356-0298, USA.
authors.forename: Shawn A
authors.initials: SA
authors.lastname: Stasko
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hardin
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Smith
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Moylan
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reid
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003964:Diaphragm / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053580:Muscle Strength / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: cytokines; diaphragm; inflammation; oxidative stress; weakness
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