Dysfunctional Nrf2-Keap1 redox signaling in skeletal muscle of the sedentary old

Free Radic Biol Med. 2010 Nov 30;49(10):1487-93. doi: 10.1016/j.freeradbiomed.2010.08.010. Epub 2010 Aug 11.


The role of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) redox signaling has not been characterized in human skeletal muscle despite an extensive delineation of oxidative stress in the etiology of aging and sarcopenia. We assessed whether the age-associated decline in antioxidant response is due, at least in part, to dysfunction in Nrf2-Keap1 redox signaling. We also evaluated whether an active lifestyle can conserve skeletal muscle cellular redox status via activation of Nrf2-Keap1 signaling. Here we show that a recreationally active lifestyle is associated with the activation of upstream modulators that induce the Nrf2-mediated antioxidant response cascade in skeletal muscle of the elderly. Conversely, a sedentary lifestyle is negatively associated with these adaptations mainly because of dysregulation of Nrf2-Keap1 redox signaling that renders the intracellular environment prone to reactive oxygen species-mediated toxicity. Our results indicate that an active lifestyle is an important determinant of cellular redox status. We propose that the metabolic induction of Nrf2-Keap1 redox signaling promises to be a viable therapy for attenuating oxidative stress-mediated damage in skeletal muscle associated with physical inactivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Line
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Kelch-Like ECH-Associated Protein 1
  • Lipid Peroxidation
  • Male
  • Mice
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • NF-E2-Related Factor 2 / physiology*
  • Osteoarthritis, Knee / physiopathology
  • Oxidation-Reduction
  • Sedentary Behavior*
  • Signal Transduction / physiology*


  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2