TNF signals via neuronal-type nitric oxide synthase and reactive oxygen species to depress specific force of skeletal muscle

Shawn A. Stasko, Brian J. Hardin, Jeffrey D. Smith, Jennifer S. Moylan, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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 neuronaltype NO synthase (nNOS) to depress specific force, and 2) musclederived 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.

Original languageEnglish
Pages (from-to)1629-1636
Number of pages8
JournalJournal of Applied Physiology
Issue number11
StatePublished - Jun 1 2013


  • Cytokines
  • Diaphragm
  • Inflammation
  • Oxidative stress
  • Weakness

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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