TY - JOUR
T1 - Disruption of Nrf2/ARE signaling impairs antioxidant mechanisms and promotes cell degradation pathways in aged skeletal muscle
AU - Miller, Corey J.
AU - Gounder, Sellamuthu S.
AU - Kannan, Sankaranarayanan
AU - Goutam, Karan
AU - Muthusamy, Vasanthi R.
AU - Firpo, Matthew A.
AU - Symons, J. David
AU - Paine, Robert
AU - Hoidal, John R.
AU - Rajasekaran, Namakkal Soorappan
N1 - Funding Information:
This work is supported by Center on Aging (CoA), Utah-Pilot Grant Program Award, Beginning Grant-In Aid from the AHA ( 086501F ) and University of Utah Interdisciplinary Seed Grant to Namakkal Soorappan Rajasekaran. Nrf2−/− mice, primers and protocol for genotyping were kindly provided by Dr. Li Wang. We are grateful to Dr. Mark A. Supiano (Director of Center on Aging) for his support and valuable comments on this project. We also thank Dr. John Michael, Chief-Division of Cardiology for the seed-funding support.
PY - 2012/6
Y1 - 2012/6
N2 - 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< 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 (> 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.
AB - 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< 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 (> 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.
KW - ARE-signaling
KW - Aging
KW - EPR
KW - Nrf2
KW - ROS
KW - Ubiquitination
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U2 - 10.1016/j.bbadis.2012.02.007
DO - 10.1016/j.bbadis.2012.02.007
M3 - Article
C2 - 22366763
AN - SCOPUS:84859033290
SN - 0925-4439
VL - 1822
SP - 1038
EP - 1050
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 6
ER -