Nuclear factor erythroid‐derived 2‐like 2 (NFE2L2, Nrf2) mediates exercise‐induced mitochondrial biogenesis and the anti‐oxidant response in mice
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Key points: Reactive oxygen species (ROS) and nitric oxide (NO) regulate exercise‐induced nuclear factor erythroid 2‐related factor 2 (NFE2L2) expression in skeletal muscle. NFE2L2 is required for acute exercise‐induced increases in skeletal muscle mitochondrial biogenesis genes, such as nuclear respiratory factor 1 (NRF‐1) and mitochondrial transcription factor A, and anti‐oxidant genes, such as superoxide dismutase (SOD)1, SOD2 and catalase. Following exercise training mice with impaired NFE2L2 expression have reduced exercise performance, energy expenditure, mitochondrial volume and anti‐oxidant activity. In muscle cells, ROS and NO can regulate mitochondrial biogenesis via a NFE2L2/NRF‐1‐dependent pathway. Regular exercise induces adaptations to skeletal muscle, which can include mitochondrial biogenesis and enhanced anti‐oxidant reserves. These adaptations and others are at least partly responsible for the improved health of physically active individuals. Reactive oxygen species (ROS) and nitric oxide (NO) are produced during exercise and may mediate the adaptive response to exercise in skeletal muscle. However, the mechanisms through which they act are unclear. In the present study, we aimed to determine the role of the redox‐sensitive transcription factor nuclear factor erythroid‐derived 2‐like 2 (NFE2L2) in acute exercise‐ and training‐induced mitochondrial biogenesis and the anti‐oxidant response. We report that ROS and NO regulate acute exercise‐induced expression of NFE2L2 in mouse skeletal muscle and muscle cells, and that deficiency in NFE2L2 prevents normal acute treadmill exercise‐induced increases in mRNA of the mitochondrial biogenesis markers, nuclear respiratory factor 1 (NRF‐1) and mitochondrial transcription factor A (mtTFA), and the anti‐oxidants superoxide dismutase (SOD) 1 and 2, as well as catalase, in mouse gastrocnemius muscle. Furthermore, after 5 weeks of treadmill exercise training, mice deficient in NFE2L2 had reduced exercise capacity and whole body energy expenditure, as well as skeletal muscle mitochondrial mass and SOD activity, compared to wild‐type littermates. In C2C12 myoblasts, acute treatment with exogenous H 2 O 2 (ROS)‐ and diethylenetriamine/NO adduct (NO donor) induced increases in mtTFA, which was prevented by small interfering RNA and short hairpin RNA knockdown of either NFE2L2 or NRF‐1. Our results suggest that, during exercise, ROS and NO can act via NFE2L2 to functionally regulate skeletal muscle mitochondrial biogenesis and anti‐oxidant defence gene expression.
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Antioxidant supplements or the deletion of NFE2L2 can block acute exercise-induced increases in PGC1α and mitochondrial biogenesis.
“Previous studies have shown that antioxidant supplements or the deletion of NFE2L2 can block acute exercise–induced increases in PGC1α and mitochondrial biogenesis (5–7).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [7]
NFE2L2 is required for the induction of mitochondrial biogenesis after exercise and for optimal exercise performance.
“NFE2L2 is thought to be required for the induction of mitochondrial biogenesis after exercise and for optimal exercise performance (3, 7).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [7]
Exercise induces Nfe2l2 gene expression, whereas ROS generated during exercise would be expected to increase NFE2L2 stability.
“Exercise induces Nfe2l2 gene expression (7), whereas ROS generated during exercise would be expected to increase NFE2L2 stability (4, 30).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [7]
Contracting muscle generates ROS and this is accompanied by increased antioxidant defense orchestrated by NFE2L2.
“It is well established that contracting muscle generates ROS and that this is accompanied by increased antioxidant defense orchestrated by NFE2L2 (2, 7, 36).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [7]
The stress imposed by exercise training is recognized as the most effective stimulus for mitochondrial biogenesis as part of redox-sensitive adaptation, resulting in enhanced mitochondrial function across the life course.
“Indeed, the stress imposed by exercise training is recognized as the most effective stimulus for mitochondrial biogenesis as part of redox-sensitive adaptation [96,97,98], resulting in enhanced mitochondrial function across the life course [99,100].”
From Role of Age-Related Mitochondrial Dysfunction in Sarcopenia (2020) · cites this paper as [99]
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BackgroundExercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle
Bouvière, J., Fortunato, R. S., Dupuy, C., Werneck‐de‐Castro, J. P., de Carvalho, D. P., & Louzada, R. A. N. (2021) · Antioxidants · doi:10.3390/antiox10040537 · Cited by 175 · see citing works
“ROS induced by physical exercise may promote the dissociation of the NRF2-Keap1 complex through the oxidation of cysteines 273 and 288 on Keap1 [66], avoiding the proteasomal degradation and then translocating NRF2 to the nucleus, activating the antioxidant-responsive element (ARE)-dependent gene and mitochondrial bio…”
BackgroundMitohormesis, an Antiaging Paradigm
Bárcena, C., Mayoral, P., & Quirós, P. M. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.05.002 · Cited by 167 · see citing works
Antioxidant and Adaptative Response Mediated by Nrf2 during Physical Exercise
Vargas-Mendoza, N., Morales‐González, Á., Madrigal‐Santillán, E., Madrigal‐Bujaidar, E., Álvarez‐González, I., García-Melo, L. F., Anguiano‐Robledo, L., Fregoso-Aguilar, T. A., & Morales‐González, J. A. (2019) · Antioxidants · doi:10.3390/antiox8060196 · Cited by 163 · see citing works
“This effect of physical exercise allows for higher deposits of reduced glutathione (GSH) in muscle [126].”
BackgroundHuang, D.-D., Fan, S.-D., Chen, X.-Y., Yan, X.-L., Zhang, X.-Z., Ma, B.-W., Yu, D.-Y., Xiao, W.-Y., Zhuang, C.-L., & Yu, Z. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.01.022 · Cited by 162 · see citing works
“With regard to the skeletal muscle, Nrf2 has been reported to mediate exercise-induced mitochondrial biogenesis in mice (Merry and Ristow, 2016).”
The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure
Galiè, M., Covi, V., Tabaracci, G., & Malatesta, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20164009 · Cited by 177 · see citing works
“Nrf2 has been shown to stimulate mitochondrial biogenesis through the activation of nuclear respiratory factor-1 (NRF-1) in cardiomyocytes [117,118].”
BackgroundMediators of Physical Activity Protection against ROS-Linked Skeletal Muscle Damage
Meo, S. D., Napolitano, G., & Venditti, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20123024 · Cited by 146 · see citing works
Mitochondrial-derived peptides in energy metabolism
Merry, T. L., Chan, A., Woodhead, J. S. T., Reynolds, J. C., Kumagai, H., Kim, S.-J., & Lee, C. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00249.2020 · Cited by 141 · see citing works
Transcription factor NRF2 as a promising therapeutic target for Alzheimer’s disease
Qu, Z., Sun, J., Zhang, W., Yu, J., & Zhuang, C. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.06.028 · Cited by 140 · see citing works
Redox basis of exercise physiology
Margaritelis, N. V., Paschalis, V., Theodorou, A. A., Kyparos, A., & Nikolaidis, M. G. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101499 · Cited by 129 · see citing works
Bernard, K. F., Logsdon, N. J., Miguel, V., Benavides, G. A., Zhang, J., Carter, A. B., Darley-Usmar, V. M., & Thannickal, V. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.752261 · Cited by 115 · see citing works
Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions
Tarnacka, B., Jopowicz, A., & Maślińska, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157820 · Cited by 115 · see citing works
“Additionally, Mn-induced neurodegeneration is regulated by the initiation of several transcription factors, including the expression of human nuclear factor erythroidderived 2-like 2 (NRF2), which is involved in mitochondrial biogenesis and antioxidant reactions [8,89,90].”
BackgroundThe Emerging Roles of Ferroptosis in Huntington’s Disease
Mi, Y., Gao, X., Xu, H., Cui, Y., Zhang, Y., & Gou, X. (2019) · NeuroMolecular Medicine · doi:10.1007/s12017-018-8518-6 · Cited by 113 · see citing works
Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance
Xirouchaki, C. E., Jia, Y., McGrath, M. J., Greatorex, S., Tran, M., Merry, T. L., Hong, D., Eramo, M. J., Broome, S. C., Woodhead, J. S. T., et al. (2021) · Science Advances · doi:10.1126/sciadv.abl4988 · Cited by 107 · see citing works
“NFE2L2 is thought to be required for the induction of mitochondrial biogenesis after exercise and for optimal exercise performance (3, 7).”
BackgroundInfluentialSelf-citationHealth Effects of Coffee: Mechanism Unraveled?
Kolb, H., Kempf, K., & Martin, S. (2020) · Nutrients · doi:10.3390/nu12061842 · Cited by 105 · see citing works
Effect of Running Exercise on Oxidative Stress Biomarkers: A Systematic Review
Thirupathi, A., Pinho, R. A., Ugbolue, U. C., He, Y., Meng, Y., & Gu, Y. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2020.610112 · Cited by 85 · see citing works
“A single bout of exercise has been observed to increase the Nrf2 gene expression in wild type mice (Merry and Ristow, 2016).”
BackgroundResultInfluentialGlutathione and Nitric Oxide: Key Team Players in Use and Disuse of Skeletal Muscle
Baldelli, S., Ciccarone, F., Limongi, D., Checconi, P., Palamara, A. T., & Ciriolo, M. R. (2019) · Nutrients · doi:10.3390/nu11102318 · Cited by 83 · see citing works
“Another pathway is shared with ROS by the activation of NFE2L2 expression, which is the master regulator of antioxidant response upon oxidative burst and mitochondrial biogenesis upon exercise in muscle [75].”
BackgroundMitochondrial Quality Control and Cellular Proteostasis: Two Sides of the Same Coin
Quiles, J. M., & Gustafsson, Å. B. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00515 · Cited by 84 · see citing works
“Nrf2 promotes the expression of biogenesis genes Nrf-1 (Merry and Ristow, 2016) and Tfam (Wu et al., 2016) as well as mitophagy factors p62/SQSTM1 (Jain et al., 2010) and DCT-1 (BNIP3 ortholog) (Palikaras et al., 2015).”
BackgroundSanyal, T., Bhattacharjee, P., Paul, S., & Bhattacharjee, P. (2020) · Frontiers in Public Health · doi:10.3389/fpubh.2020.00464 · Cited by 83 · see citing works
Rajan, S., Tryphena, K. P., Khan, S. S., Vora, L. K., Srivastava, S., Singh, S. B., & Khatri, D. K. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101915 · Cited by 81 · see citing works
Tkaczenko, H., & Kurhaluk, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031098 · Cited by 80 · see citing works
“Furthermore, in muscle cells, ROS and NO influence mitochondrial biogenesis via the NFE2L2/NRF-1 pathway [15].”
Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition
Vargas-Mendoza, N., Ángeles-Valencia, M., Morales‐González, Á., Madrigal‐Santillán, E., Morales-Martínez, M., Madrigal‐Bujaidar, E., Álvarez‐González, I., Gutiérrez‐Salinas, J., Esquivel-Chirino, C., Chamorro, G., et al. (2021) · Life · doi:10.3390/life11111269 · Cited by 83 · see citing works
“These results suggest that ROS and NO are able to regulate the Nrf2 pathway to stimulate mitochondrial biogenesis and the expression of antioxidant protection genes [68].”
BackgroundMenshikova, E. V., Ritov, V. B., Dube, J. J., Amati, F., Stefanovic-Racic, M., Toledo, F. G. S., Coen, P. M., & Goodpaster, B. H. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw328 · Cited by 80 · see citing works
Therapeutic Insights on Ferroptosis in Parkinson's disease
Thapa, K., Khan, H., Kanojia, N., Singh, T. G., Kaur, A., & Kaur, G. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175133 · Cited by 78 · see citing works
Exercise, redox homeostasis and the epigenetic landscape
Dimauro, I., Paronetto, M. P., & Caporossi, D. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101477 · Cited by 76 · see citing works
Bento‐Pereira, C., & Dinkova‐Kostova, A. T. (2020) · Medicinal Research Reviews · doi:10.1002/med.21714 · Cited by 78 · see citing works
Mayer, C., Riera‐Ponsati, L., Kauppinen, S., Klitgaard, H., Erler, J. T., & Hansen, S. N. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1437939 · Cited by 75 · see citing works
Nrf2 as a regulator of energy metabolism and mitochondrial function
Luchkova, A. Y., Mata, A., & Cadenas, S. (2024) · FEBS Letters · doi:10.1002/1873-3468.14993 · Cited by 80 · see citing works
“Nrf2 has been shown to increase gene expression of the transcription factors nuclear respiratory factor 1 (NRF-1) and peroxisome proliferator-activated receptor gamma coactivator-1 a (PGC-1 a ), which promote mitochondrial biogenesis [105 – 107].”
Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease
Kaidery, N. A., Ahuja, M., & Thomas, B. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.103413 · Cited by 75 · see citing works
“Even exercise-induced increases in mitochondrial biogenesis and expression of antioxidant genes, such as SOD1 and 2 and catalase in skeletal muscle is mediated by ROS- and RNS-induced Nrf2 activation (Merry and Ristow, 2016).”
BackgroundExercise-Induced Mitohormesis for the Maintenance of Skeletal Muscle and Healthspan Extension
Musci, R., Hamilton, K., & Linden, M. (2019) · Sports · doi:10.3390/sports7070170 · Cited by 73 · see citing works
“Indeed, the stress imposed by exercise training has long been recognized as the most robust stimulus for mitochondrial biogenesis, increasingly recognized as redox-sensitive adaptation [102,118,119], resulting in enhanced mitochondrial function throughout age [120,121].”
BackgroundOh, S., Komine, S., Warabi, E., Akiyama, K., Ishii, A., Ishige, K., Mizokami, Y., Kuga, K., Horie, M., Miwa, Y., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-12926-y · Cited by 70 · see citing works
Targeting the molecular & cellular pillars of human aging with exercise
Goh, J., Wong, E. S. P., Soh, J., Maier, A. B., & Kennedy, B. K. (2021) · FEBS Journal · doi:10.1111/febs.16337 · Cited by 73 · see citing works
Bathish, B., Robertson, H., Dillon, J. F., Dinkova‐Kostova, A. T., & Hayes, J. D. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.06.226 · Cited by 68 · see citing works
Cellular Pathogenesis of Hepatic Encephalopathy: An Update
Lu, K. (2023) · Biomolecules · doi:10.3390/biom13020396 · Cited by 68 · see citing works
Powers, S. K., & Schrager, M. A. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102374 · Cited by 67 · see citing works
Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise
Hancock, M., Hafstad, A. D., Nabeebaccus, A. A., Catibog, N., Logan, A., Smyrnias, I., Hansen, S. S., Lanner, J., Schröder, K., Murphy, M. P., et al. (2018) · eLife · doi:10.7554/elife.41044 · Cited by 64 · see citing works
Henríquez‐Olguín, C., Meneses‐Valdés, R., & Jensen, T. E. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101473 · Cited by 65 · see citing works
Hua, W., Li, S., Luo, R., Wu, X., Zhang, Y., Liao, Z., Song, Y., Wang, K., Zhao, K., Yang, S., et al. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165575 · Cited by 63 · see citing works
Egbujor, M. C., Saha, S., Buttari, B., Profumo, E., & Saso, L. (2021) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2021.1901578 · Cited by 61 · see citing works
“The activation of Nrf2 pathway was found to stimulate mitochondrial biogenesis via nuclear respiratory factor-1 (NRF-1) activation in cardiomyocytes [65].”
BackgroundIslam, H., Hood, D. A., & Gurd, B. J. (2019) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2019-0069 · Cited by 62 · see citing works
“…(Egan and Zierath 2013), increases in Nrf2 mRNA expression (and supposedly its activity (Kwak et al. 2002)) (Ballmann et al. 2014; Li et al. 2015; Merry and Ristow 2016), protein content (Wang et al. 2016), and Nrf2-ARE binding (Crilly et al. 2016) have been observed in murine and/or human…”
BackgroundFunctional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle
Gao, L., Kumar, V., Vellichirammal, N. N., Park, S., Rudebush, T. L., Yu, L., Son, W., Pekas, E. J., Wafi, A. M., Hong, J., et al. (2020) · The Journal of Physiology · doi:10.1113/jp280176 · Cited by 58 · see citing works
“Exercise performance and muscle contractility of Nrf2-deficient mice were also impaired (Crilly et al. 2016; Merry & Ristow, 2016).”
BackgroundBiesemann, N., Ried, J. S., Ding‐Pfennigdorff, D., Dietrich, A., Rudolph, C., Hahn, S., Hennerici, W., Asbrand, C., Leeuw, T., & Strübing, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-27614-8 · Cited by 59 · see citing works
Major Depressive Disorder and Gut Microbiota: Role of Physical Exercise
de Souza, P. B., Borba, L. A., de Jesus, L. C., Valverde, A. P., Gil‐Mohapel, J., & Rodrigues, A. L. S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316870 · Cited by 65 · see citing works
“This mechanism is partially mediated by an increase in reactive oxygen species (ROS), which leads to the translocation of the transcription factor Nrf2 to the nucleus, resulting in the expression of antioxidant proteins [168,169].”
BackgroundAbreu, C. C., Cardozo, L., Stockler‐Pinto, M. B., Esgalhado, M., Barboza, J. E., Frauches, R., & Mafra, D. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.09.007 · Cited by 60 · see citing works
Wafi, A. M., Hong, J., Rudebush, T., Yu, L., Hackfort, B. T., Wang, H., Schultz, H. D., Zucker, I. H., & Gao, L. (2018) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00654.2018 · Cited by 60 · see citing works
“Chronic exercise training improved exercise capacity in WT mice, whereas it impaired exercise capacity in Nrf2 KO mice (31).”
BackgroundGallego-Selles, Á., Martín-Rincón, M., Martinez‐Canton, M., Perez‐Valera, M., Martín-Rodríguez, S., Gelabert‐Rebato, M., Santana, A., Morales‐Álamo, D., Dorado, C., & Calbet, J. A. L. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101627 · Cited by 55 · see citing works
Sarcopenia, Aging and Prospective Interventional Strategies
Waltz, T. B., Fivenson, E. M., Morevati, M., Li, C., Becker, K. G., Bohr, V. A., & Fang, E. F. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867324666170801095850 · Cited by 54 · see citing works
Zhou, S., Taskintuna, K., Hum, J., Gulati, J., Olaya, S., Steinman, J., & Golestaneh, N. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06762-y · Cited by 54 · see citing works
“NFE2L2 can regulate the antioxidant response to protect cells against oxidative damage by inducing the production of antioxidant enzymes, including superoxide dismutase 1/2 (SOD1/2) and catalase (CAT) [45, 46].”
Physical-Exercise-Induced Antioxidant Effects on the Brain and Skeletal Muscle
Souza, J., da Silva, R. A., Scheffer, D. D. L., dos Santos, R. P., Solano, A. F., Barros, L., Budde, H., Trostchansky, A., & Latini, A. (2022) · Antioxidants · doi:10.3390/antiox11050826 · Cited by 52 · see citing works
Zweig, J. A., Caruso, M. A., Brandes, M. S., & Gray, N. E. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110767 · Cited by 52 · see citing works
“These results are consistent with previous reports where loss of NRF2 has showed to impair mitochondrial function in a variety of tissue types including the brain, liver and heart of NRF2KO mice [65] and reduced mitochondrial number in skeletal muscle [71].”
ResultTargeting of stress response pathways in the prevention and treatment of cancer
Zelenka, J., Koncošová, M., & Ruml, T. (2018) · Biotechnology Advances · doi:10.1016/j.biotechadv.2018.01.007 · Cited by 50 · see citing works
Redox Signaling in Widespread Health Benefits of Exercise
Louzada, R. A. N., Bouvière, J., Matta, L., Werneck‐de‐Castro, J. P., Dupuy, C., de Carvalho, D. P., & Fortunato, R. S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7949 · Cited by 47 · see citing works
“Regular aerobic exercise in rodent models has consistently been shown to activate Nrf2 signaling in multiple tissues, including skeletal muscle (111), kidney (122), brain (162), liver (135), and myocardium (145), which leads to the upregulation of endogenous antioxidant defenses and an overall…”
Reductive stress in striated muscle cells
Bellezza, I., Riuzzi, F., Chiappalupi, S., Arcuri, C., Giambanco, I., Sorci, G., & Donato, R. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03476-0 · Cited by 43 · see citing works
“Indeed, physical exercise increases Nrf2 transcriptional activity [162] which is required for the maintenance of basal mitochondrial function and the normal increase in specific mitochondrial proteins in response to training.”
BackgroundNrf2, cellular redox regulation, and neurologic implications
Benarroch, E. E. (2017) · Neurology · doi:10.1212/wnl.0000000000003946 · Cited by 42 · see citing works
Brendel, H., Shahid, A., Hofmann, A., Mittag, J., Bornstein, S. R., Morawietz, H., & Brunßen, C. (2019) · Cardiovascular Research · doi:10.1093/cvr/cvz322 · Cited by 42 · see citing works
Regulatory networks coordinating mitochondrial quality control in skeletal muscle
Slavin, M. B., Memme, J. M., Oliveira, A. N., Moradi, N., & Hood, D. A. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00065.2022 · Cited by 40 · see citing works
Exercise-induced Nrf2 activation increases antioxidant defenses in skeletal muscles
Powers, S. K., Lategan-Potgieter, R., & Goldstein, E. R. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.07.041 · Cited by 41 · see citing works
Yu, W., Zhang, X., Wu, H., Zhou, Q., Wang, Z., Liu, R., Liu, J., Wang, X., & Hai, C. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/1818575 · Cited by 41 · see citing works
An update on the bridging factors connecting autophagy and Nrf2 antioxidant pathway
Ning, B., Hang, S.-Q., Zhang, W., Mao, C.-W., & Li, D. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1232241 · Cited by 37 · see citing works
Bhawe, K. M., Felty, Q. H., Yoo, C., Ehtesham, N. Z., Hasnain, S. E., Singh, V. P., Mohapatra, I., & Roy, D. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01979-2 · Cited by 40 · see citing works
Onoki, T., Izumi, Y., Takahashi, M., Murakami, S., Matsumaru, D., Ohta, N., Wati, S. M., Hatanaka, N., Katsuoka, F., Okutsu, M., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101966 · Cited by 39 · see citing works
Islam, H., Bonafiglia, J. T., Turnbull, P. C., Simpson, C. A., Perry, C. G. R., & Gurd, B. J. (2019) · European Journal of Applied Physiology · doi:10.1007/s00421-019-04259-7 · Cited by 39 · see citing works
The Role of Nrf2 in Skeletal Muscle on Exercise Capacity
Kitaoka, Y. (2021) · Antioxidants · doi:10.3390/antiox10111712 · Cited by 37 · see citing works
“reported that commercially available Nrf2 antibodies were unable to detect the single band corresponding to Nrf2 in muscle lysates at correct molecular weight, that was not seen in lysates from Nrf2 KO mice [36].”
BackgroundInfluentialMitochondrial biology in airway pathogenesis and the role of NRF2
Cho, H., & Kleeberger, S. R. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-019-01182-5 · Cited by 38 · see citing works
PGC‐1α protects from myocardial ischaemia‐reperfusion injury by regulating mitonuclear communication
Li, Y., Jiao, Y., Liu, Y., Fu, J., Sun, L., & Su, J. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16236 · Cited by 38 · see citing works
Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds
Patanè, G. T., Putaggio, S., Tellone, E., Barreca, D., Ficarra, S., Maffei, C., Calderaro, A., & Laganà, G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417279 · Cited by 38 · see citing works
“…activity counteracts the increased ROS production in the mitochondria and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1 α , as well as by promoting purine nucleotide biosynthesis [65,66].”
BackgroundMahmoud, A. M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-4307-9_12 · Cited by 37 · see citing works
Coleman, V., Sa-nguanmoo, P., Koenig, J., Schulz, T., Grune, T., Klaus, S., Kipp, A., & Ost, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-20901-4 · Cited by 39 · see citing works
Ye, C., Geng, Z., Zhang, L., Zheng, F., Zhou, Y., Zhu, G., & Xiong, X. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-00875-w · Cited by 37 · see citing works
“Nrf2 is considered to be a cytoprotective factor that regulates the expression of genes that code for anti-oxidative and anti-inflammatory responses [28, 29].”
BackgroundTaylor, D. F., & Bishop, D. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031517 · Cited by 37 · see citing works
Zoccarato, A., Smyrnias, I., Reumiller, C. M., Hafstad, A. D., Chong, M., Richards, D. A., Santos, C. X. C., Visnagri, A., Verma, S., Bromage, D. I., et al. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae250 · Cited by 36 · see citing works
“…in cardiac pathological stress and HF. NRF2 is described to potentially affect several other metabolic processes, for example, mitochondrial biogenesis 59,60 and lipid metabolism; 61,62 hence, future work is also needed to define the relative role of PPP activation vs. other metabolic effects.”
Gao, L., Wang, H., Tian, C., & Zucker, I. H. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000257 · Cited by 37 · see citing works
NRF2 in age-related musculoskeletal diseases: Role and treatment prospects
Zhang, X., Li, H., Chen, L., Wu, Y., & Li, Y. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.101180 · Cited by 38 · see citing works
“95 This may also be why lifelong physical exercise reverses age-related skeletal muscle loss.”
BackgroundTaati, B., Arazi, H., & Suzuki, K. (2020) · Antioxidants · doi:10.3390/antiox9090777 · Cited by 36 · see citing works
“It has been established that impaired Nrf2 expression reduces exercise performance, energy expenditure, mitochondrial volume and antioxidant activity following exercise training [65].”
BackgroundPeroxiredoxin 2 is required for the redox mediated adaptation to exercise
Qin, X., Casas-Martinez, J. C., Zarzuela, E., Muñoz, J., Miranda‐Vizuete, A., Goljanek‐Whysall, K., & McDonagh, B. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102631 · Cited by 33 · see citing works
“Site specific exercise induced ROS generation is required for a range of metabolic and cellular events including mitochondrial biogenesis [9] and Glut4 translocation 10 to the plasma membrane regulating glucose uptake during exercise [8].”
BackgroundKitaoka, Y., Takeda, K., Tamura, Y., Fujimaki, S., Takemasa, T., & Hatta, H. (2016) · Physiological Reports · doi:10.14814/phy2.13064 · Cited by 34 · see citing works
Differential effects of vitamin C or protandim on skeletal muscle adaptation to exercise
Bruns, D. R., Ehrlicher, S. E., Khademi, S., Biela, L. M., Peelor, F. F., Miller, B. F., & Hamilton, K. L. (2018) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00277.2018 · Cited by 33 · see citing works
Pomatto, L. C. D., Dill, T., Carboneau, L., Levan, S., Kato, J. I., Mercken, E. M., Pearson, K. J., Bernier, M., & de Cabo, R. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.01.005 · Cited by 31 · see citing works
“To explore the growing evidence suggests possible interplay between Nrf2 and the mitochondria (35), in part through increased expression of PGC-1α a key transcriptional regulator of mitochondrial biogenesis (76, 77), that decreases with age (78, 79) and disease (80).”
BackgroundAerobic exercise training partially reverses the impairment of Nrf2 activation in older humans
Ostrom, E. L., & Traustadóttir, T. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.08.016 · Cited by 33 · see citing works
“Many of the beneficial effects rely on redox-dependent cell signaling mechanisms to induce exercise adaptations [46].”
BackgroundOzone Activates the Nrf2 Pathway and Improves Preservation of Explanted Adipose Tissue In Vitro
Cisterna, B., Costanzo, M., Nodari, A., Galiè, M., Zanzoni, S., Bernardi, P., Covi, V., Tabaracci, G., & Malatesta, M. (2020) · Antioxidants · doi:10.3390/antiox9100989 · Cited by 32 · see citing works
“Among its various functions, Nrf2 is involved in mitochondrial biogenesis [38,39]; moreover, mitochondrial respiration and ATP synthesis are strictly related to Nrf2/Keap1 levels, which play a crucial role in the functional modulation of mitochondria under stress conditions in order to preserve cell redox homeostasis…”
BackgroundMitigation of Cardiovascular Disease and Toxicity through NRF2 Signalling
Roberts, J. A., Rainbow, R. D., & Sharma, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076723 · Cited by 34 · see citing works
“In fact, co-activation in the form of a positive feedback loop has been suggested as a point of crosstalk between NRF2 and PGC1α pathways with a consequential multifactorial activation of mitochondrial biogenesis and maintenance such as activating mitochondrial transcription factor A (TFAM), which contributes to mitoc…”
BackgroundHenríquez‐Olguín, C., Meneses‐Valdés, R., Raun, S. H., Gallero, S., Knudsen, J. R., Li, Z., Li, J., Sylow, L., Jaimovich, E., & Jensen, T. E. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102842 · Cited by 32 · see citing works
- Authors
- Merry, T. L., & Ristow, M.
- Affiliations
- University of Auckland (NZ)
- ETH Zurich (CH)
- Corresponding author
- Merry, Troy L.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2016-05-27
- Volume
- 594
- Issue
- 18
- Pages
- 5195-5207
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC5023720
- OpenAlex
- W2339478196
- Cited by
- 246
- References
- 55
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 21 · 2023: 25 · 2022: 25 · 2021: 32 · 2020: 38 · 2019: 27 · 2018: 21 · 2017: 11 · 2016: 3
- FWCI
- 22.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kanton Zürich
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- Nrf2, exercise training, skeletal muscle, mitochondrial biogenesis, reactive oxygen species, nitric oxide, antioxidant response, NRF1, TFAM, superoxide dismutase, catalase, exercise capacity, energy expenditure, mitochondrial mass, redox-sensitive transcription factors, C2C12 myoblasts, oxidative stress
- MeSH terms
- Superoxide Dismutase-1, Superoxide Dismutase 2, Animals, Organelle Biogenesis, Catalase, Cell Line, Citrate (si)-Synthase, DNA-Binding Proteins, Glutathione, Glutathione Reductase, Glutathione Transferase, Male, Mice, Inbred C57BL, Mitochondria, Nitric Oxide, Physical Conditioning, Animal, Superoxide Dismutase, Transcription Factors, Gene Expression, Reactive Oxygen Species, Mice, Knockout, Homeodomain Proteins, Muscle, Skeletal, Mitochondrial Proteins, Muscle Cells, Protein Carbonylation, Nuclear Respiratory Factor 1, NF-E2-Related Factor 2
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