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

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• 作者：Corey J. Miller^a ; ¹ ; Sellamuthu S. Gounder^a ; ¹ ; Sankaranarayanan Kannan^b ; Karan Goutam^c ; Vasanthi R. Muthusamy^a ; Matthew A. Firpo^d ; J. David Symons^e ; Robert Paine III^f ; John R. Hoidal^f ; Namakkal Soorappan Rajasekaran^a ; ^f ; ^{Raj.Soorappan@hsc.utah.edu}
• 关键词：Nrf2 ; ARE-signaling ; ROS ; EPR ; Ubiquitination ; Aging
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2012
• 期刊代码：19_09254439
• 类别：bio
• 出版时间：June, 2012
• 卷：1822
• 期：6
• 页码：1038-1050
• 文件大小：2111 K

摘要

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鈭?鈭?mice. Interestingly, mRNA and protein levels of NADH Quinone Oxidase-1 were dramatically (*P < 0.001) decreased in Nrf2鈭?鈭?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 (> 24 months) had a significant increase in ROS along with a decrease in glutathione (GSH) levels and impaired antioxidants in Nrf2鈭?鈭?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鈭?鈭?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.