Disruption of Nrf2/ARE signaling impairs antioxidant mechanisms and promotes cell degradation pathways in aged skeletal muscle

作者：Miller Corey J; Gounder Sellamuthu S; Kannan Sankaranarayanan; Goutam Karan; Muthusamy Vasanthi R; Firpo Matthew A; Symons J David; Paine Robert III; Hoidal John R; Rajasekaran Namakkal Soorappan^*

来源：Biochimica et Biophysica Acta-Molecular Basis of Disease, 2012, 1822(6): 1038-1050.

DOI：10.1016/j.bbadis.2012.02.007

• Nrf2
• ARE-signaling
• ROS
• EPR
• Ubiquitination
• Aging

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 (2 months) Nrf2-/- mice. Interestingly, mRNA and protein levels of NADH Quinone Oxidase-1 were dramatically (*P%26lt;0.001) decreased in Nrf2-/- SM when compared to WT at 2 months of age, suggesting central regulation of NQO1 occurs through Nrf2. Subsequent analysis of the Nrf2-dependent transcription and translation showed that the aged mice (%26gt;24 months) 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.

• 出版日期2012-6