title: Disruption of Nrf2/ARE signaling impairs antioxidant mechanisms and promotes cell degradation pathways in aged skeletal muscle.
abstract: Age-associated decline in antioxidant potential and accumulation of reactive oxygen/nitrogen species are primary causes for multiple health problems, including muscular dystrophy and sarcopenia. The role of the nuclear erythroid-2-p45-related factor-2 (Nrf2) signaling has been implicated in antioxidant gene regulation. Here, we investigated the loss-of-function mechanisms for age-dependent regulation of Nrf2/ARE (Antioxidant Response Element) signaling in skeletal muscle (SM). Under basal physiological conditions, disruption of Nrf2 showed minimal effects on antioxidant defenses in young (2months) Nrf2-/- mice. Interestingly, mRNA and protein levels of NADH Quinone Oxidase-1 were dramatically (*P<0.001) decreased in Nrf2-/- SM when compared to WT at 2months of age, suggesting central regulation of NQO1 occurs through Nrf2. Subsequent analysis of the Nrf2-dependent transcription and translation showed that the aged mice (>24months) had a significant increase in ROS along with a decrease in glutathione (GSH) levels and impaired antioxidants in Nrf2-/- when compared to WT SM. Further, disruption of Nrf2 appears to induce oxidative stress (increased ROS, HNE-positive proteins), ubiquitination and pro-apoptotic signals in the aged SM of Nrf2-/- mice. These results indicate a direct role for Nrf2/ARE signaling on impairment of antioxidants, which contribute to muscle degradation pathways upon aging. Our findings conclude that though the loss of Nrf2 is not amenable at younger age; it could severely affect the SM defenses upon aging. Thus, Nrf2 signaling might be a potential therapeutic target to protect the SM from age-dependent accumulation of ROS by rescuing redox homeostasis to prevent age-related muscle disorders such as sarcopenia and myopathy.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Miller
authors.forename: Sellamuthu S
authors.initials: SS
authors.lastname: Gounder
authors.forename: Sankaranarayanan
authors.initials: S
authors.lastname: Kannan
authors.forename: Karan
authors.initials: K
authors.lastname: Goutam
authors.forename: Vasanthi R
authors.initials: VR
authors.lastname: Muthusamy
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firpo
authors.forename: J David
authors.initials: JD
authors.lastname: Symons
authors.forename: Robert
authors.initials: R
authors.lastname: Paine
authors.forename: John R
authors.initials: JR
authors.lastname: Hoidal
authors.forename: Namakkal Soorappan
authors.initials: NS
authors.lastname: Rajasekaran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements; D055948:Sarcopenia / Q000473:pathology; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005978:Glutathione