Disruption of Nrf2/ARE signaling impairs antioxidant mechanisms and promotes cell degradation pathways in aged skeletal muscle.
Biochim Biophys Acta
; 1822(6): 1038-50, 2012 Jun.
Article
em En
| MEDLINE
| ID: mdl-22366763
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.
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Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
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Transdução de Sinais
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Estresse Oxidativo
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Músculo Esquelético
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Elementos de Resposta
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Fator 2 Relacionado a NF-E2
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article