Dysfunctional Nrf2-Keap1 redox signaling in skeletal muscle of the sedentary old.
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.
Safdar
Adeel
A
Department of Kinesiology, McMaster University, Hamilton, ON L8N 3Z5, Canada.
deBeer
Justin
J
Tarnopolsky
Mark A
MA
D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D020370:Osteoarthritis, Knee / Q000503:physiopathology; D010084:Oxidation-Reduction; D057185:Sedentary Behavior; D015398:Signal Transduction / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2