| First Author | Stasko SA | Year | 2013 |
| Journal | J Appl Physiol (1985) | Volume | 114 |
| Issue | 11 | Pages | 1629-36 |
| PubMed ID | 23558387 | Mgi Jnum | J:329089 |
| Mgi Id | MGI:6852196 | Doi | 10.1152/japplphysiol.00871.2012 |
| Citation | Stasko SA, et al. (2013) TNF signals via neuronal-type nitric oxide synthase and reactive oxygen species to depress specific force of skeletal muscle. J Appl Physiol (1985) 114(11):1629-36 |
| abstractText | 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(omega)-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. |
