Dysfunctional Nrf2–Keap1 redox signaling in skeletal muscle of the sedentary old

Safdar, Adeel; DeBeer, Justin; Tarnopolsky, Mark A.

doi:10.1016/j.freeradbiomed.2010.08.010

Cited by 133 publications

(100 citation statements)

References 53 publications

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“…Aging is characterized by a loss of muscle mass (sarcopenia) and brain atrophy (9,10,27,28). Consistent with the causal role of mtDNA mutations in multiorgan pathology in PolG mice, we found significant reductions in skeletal muscle (25,26,29) and brain mass in PolG-SED mice compared with WT mice ( Fig.…”

Section: Endurance Exercise Mitigated Multisystem Degeneration In Polgsupporting

confidence: 83%

“…Mitochondrial abnormalities and mtDNA mutagenesis are well-established intrinsic instigators that drive multisystem degeneration, stress intolerance, and energy deficits during aging in humans (3), monkeys (4), and rodents (5). Reduced mitochondrial quality and content in multiple tissues is also implicated in several aging-associated conditions, including cancer, obesity, cardiovascular diseases, hypertension, type 2 diabetes, osteoporosis, and dementia, as well as in the pathogenesis of neurometabolic syndromes, psychiatric disorders, end-stage renal disease, and mitochondrial cytopathies (6)(7)(8)(9)(10). Current treatment strategies for conditions associated with mitochondrial dysfunction address the secondary symptoms but not the deficiency itself (11).…”

mentioning

confidence: 99%

“…There is incontrovertible evidence from epidemiologic studies that endurance exercise extends life expectancy and reduces the risk of chronic diseases (7)(8)(9)(10)(13)(14)(15)(16)(17)(18)(19)(20)(21). Endurance exercise is the most potent physiological inducer of mitochondrial biogenesis in skeletal muscle (12) and also has profound effects on metabolism in various other tissues, including heart, brain, adipose tissue, and liver (22,23).…”

mentioning

confidence: 99%

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Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

Safdar

Bourgeois²,

Ogborn

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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323

327

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A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.

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Section: Endurance Exercise Mitigated Multisystem Degeneration In Polgsupporting

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

Safdar

Bourgeois²,

Ogborn

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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323

327

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“…A similar SNP has also been found in the human NRF2 gene upstream regulatory element (42), affecting NRF2 gene expression and the morbidity of acute lung injury (43). Nrf2 expression levels in SkM are decreased in sedentary old humans (44). Thus, Nrf2 expression levels in SkM appear to be influenced by age, exercise, and SNP, and these factors may affect intrinsic susceptibility or pharmacological effectiveness of targeting Nrf2 for management of diabetes mellitus.…”

Section: Discussionmentioning

confidence: 73%

The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Uruno

Furusawa

Yagishita

et al. 2013

Molecular and Cellular Biology

287

260

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e Transcription factor Nrf2 (NF-E2-related factor 2) regulates a broad cytoprotective response to environmental stresses. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. Whereas the Keap1-Nrf2 system plays important roles in oxidative stress response and metabolism, the roles Nrf2 plays in the prevention of diabetes mellitus remain elusive. Here we show that genetic activation of Nrf2 signaling by Keap1 gene hypomorphic knockdown (Keap1 flox/؊ ) markedly suppresses the onset of diabetes. When Keap1 flox/؊ mice were crossed with diabetic db/db mice, blood glucose levels became lower through improvement of both insulin secretion and insulin resistance. Keap1 flox/؊ also prevented high-calorie-diet-induced diabetes. Oral administration of the Nrf2 inducer CDDO-Im {oleanolic acid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole} also attenuated diabetes in db/db mice. Nrf2 induction altered antioxidant-, energy consumption-, and gluconeogenesis-related gene expression in metabolic tissues. Thus, the Keap1-Nrf2 system is a critical target for preventing the onset of diabetes mellitus.

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“…As discussed above, exercise stimulates Nfr-2 and NFkB, improving antioxidant defenses in decreasing free radicals. It has been suggested aging-related sedentary lifestyle is associated with impaired function of the Nfr-2 signaling pathway and increased oxidative stress (Safdar et al 2010). In fact, polymorphisms of the Nrf-2 encoding gene have been associated with endurance performance of athletes (He et al 2007;Eynon et al 2010).…”

Section: Tac In Aging and Detraining: Is The Lack Of Exercise The Orimentioning

confidence: 99%

Exercise modulation of total antioxidant capacity (TAC): towards a molecular signature of healthy aging

Ferrari

2011

Frontiers in Life Science

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The objective of this article was to review the biochemical basis of the total antioxidant capacity (TAC) test and its applications to exercise science and promotion of healthy aging. Measurement of TAC allows evaluation of the antioxidant content of muscle, heart and other exercise-target organs. Acute non-regular physical exercise and body exposition to higher altitude have been associated with a considerable decrease of blood TAC. However, regular practice of physical activity and exercise is associated with improved antioxidant response increasing TAC levels. TAC methodologies did not address lipophylic antioxidants and have some other limitations. However, TAC is useful as a complementary test for the evaluation of antiperoxidation assays and blood, erythrocyte and cytosolic antioxidant enzyme assays (glutathion reductase, glutathion peroxidase, superoxide dismutase and catalase). Exercise induces both molecular antioxidant and hormetic responses which have been suggested to be linked with a healthy aging.

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Dysfunctional Nrf2–Keap1 redox signaling in skeletal muscle of the sedentary old

Cited by 133 publications

References 53 publications

Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Exercise modulation of total antioxidant capacity (TAC): towards a molecular signature of healthy aging

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