Effects of Nrf2 deficiency on mitochondrial oxidative stress in aged skeletal muscle
Open accessAbstract
Oxidative stress and mitochondrial dysfunction are associated with the aging process. However, the role of nuclear factor erythroid 2 -related factor 2 (Nrf2) in skeletal muscle during aging remains to be clarified. In the current study, we assessed whether the lack of Nrf2, which is known as a master regulator of redox homeostasis, promotes age-related mitochondrial dysfunction and muscle atrophy in skeletal muscle. Here, we demonstrated that mitochondrial 4-hydroxynonenal and protein carbonyls, markers of oxidative stress, were robustly elevated in aged Nrf2 knockout (KO) mice because of the decreased expression of Nrf2-target antioxidant genes. Mitochondrial respiration declined with aging; however, there was no difference between Nrf2 KO and age-matched WT mice. Similarly, cytochrome c oxidase activity was lower in aged WT and Nrf2 KO mice compared with young WT mice. The expression of Mfn1 and Mfn2 mRNA was lower in aged Nrf2 KO muscle. Mitochondrial reactive oxygen species production per oxygen consumed was elevated in aged Nrf2 KO mice. There was no effect of Nrf2 KO on muscle mass normalized to body weight. These results suggest that Nrf2 deficiency exacerbates age-related mitochondrial oxidative stress but does not affect the decline of respiratory function in skeletal muscle.
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From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [16]
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From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [16]
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1 retracted
Sulforaphane alleviates muscular dystrophy inmdxmice by activation of Nrf2
Sun, C., Yang, C., Xue, R., Li, S., Zhang, T., Pan, L., Ma, X., Wang, L., & Li, D. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00744.2014 · Cited by 83 · see citing works
RetractedSarcopenia: European consensus on definition and diagnosis
Cruz-Jentoft, A. J., Baeyens, J. P., Bauer, J. M., Boirie, Y., Cederholm, T., Landi, F., Martin, F. C., Michel, J.-P., Rolland, Y., Schneider, S. M., et al. (2010) · Age and Ageing · doi:10.1093/ageing/afq034 · Cited by 11,601 · see citing works
Aging: a theory based on free radical and radiation chemistry
Harman, D. (1956) · Journal of Gerontology · doi:10.1093/geronj/11.3.298 · Cited by 8,567 · see citing works
Nrf2–Keap1 defines a physiologically important stress response mechanism
Motohashi, H., & Yamamoto, M. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.09.003 · Cited by 1,725 · see citing works
Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells
Spinazzi, M., Casarin, A., Pertegato, V., Salviati, L., & Angelini, C. I. (2012) · Nature Protocols · doi:10.1038/nprot.2012.058 · Cited by 989 · see citing works
Mitochondrial oxidative stress in aging and healthspan
Dai, D., Chiao, Y. A., Marcinek, D. J., Szeto, H. H., & Rabinovitch, P. S. (2014) · Longevity & Healthspan · doi:10.1186/2046-2395-3-6 · Cited by 481 · see citing works
Holmström, K. M., Baird, L., Zhang, Y., Hargreaves, I. P., Chalasani, A., Land, J. M., Stanyer, L., Yamamoto, M. P., Dinkova‐Kostova, A. T., & Abramov, A. Y. (2013) · Biology Open · doi:10.1242/bio.20134853 · Cited by 451 · see citing works
Mitochondrial function and apoptotic susceptibility in aging skeletal muscle
Chabi, B., Ljubicic, V., Menzies, K. J., Huang, J. H., Saleem, A., & Hood, D. A. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2007.00347.x · Cited by 437 · see citing works
Simple spectrophotometric assay for measuring catalase activity in biological tissues
Hadwan, M. H. (2018) · BMC Biochemistry · doi:10.1186/s12858-018-0097-5 · Cited by 377 · see citing works
Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice
Leduc-Gaudet, J.-P., Picard, M., Pelletier, F. S.-J., Sgarioto, N., Auger, M.-J., Vallée, J., Robitaille, R., St-Pierre, D. H., & Gouspillou, G. (2015) · Oncotarget · doi:10.18632/oncotarget.4235 · Cited by 273 · see citing works
Exercise Training-Induced Regulation of Mitochondrial Quality
Yan, Z., Lira, V. A., & Greene, N. P. (2012) · Exercise and Sport Sciences Reviews · doi:10.1097/jes.0b013e3182575599 · Cited by 233 · see citing works
Mitochondria, Muscle Health, and Exercise with Advancing Age
Carter, H. N., Chen, C. C. W., & Hood, D. A. (2015) · Physiology · doi:10.1152/physiol.00039.2014 · Cited by 191 · see citing works
Siegel, M. P., Kruse, S. E., Percival, J. M., Goh, J., White, C. C., Hopkins, H. C., Kavanagh, T. J., Szeto, H. H., Rabinovitch, P. S., & Marcinek, D. J. (2013) · Aging Cell · doi:10.1111/acel.12102 · Cited by 186 · see citing works
H2O2-induced mitochondrial fragmentation in C2C12 myocytes
Fan, X., Hussien, R., & Brooks, G. A. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.08.024 · Cited by 172 · see citing works
Iqbal, S., Ostojic, O., Singh, K., Joseph, A., & Hood, D. A. (2013) · Muscle & Nerve · doi:10.1002/mus.23838 · Cited by 169 · cited 1× · see citing works
“Morphologically, aging induces mitochondrial fragmentation or unusual enlargement in skeletal muscle (Iqbal et al. 2013; Leduc-Gaudet et al. 2015).”
BackgroundGenetically enhancing mitochondrial antioxidant activity improves muscle function in aging
Umanskaya, A., Santulli, G., Xie, W., Andersson, D. C., Reiken, S. R., & Marks, A. R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412754111 · Cited by 157 · see citing works
Miller, C. J., Gounder, S. S., Kannan, S., Karan, G., Muthusamy, V. R., Firpo, M. A., Symons, J. D., Paine, R., Hoidal, J. R., & Rajasekaran, N. S. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.02.007 · Cited by 146 · see citing works
Holloway, G. P., Holwerda, A. M., Miotto, P. M., Dirks, M. L., Verdijk, L. B., & van Loon, L. J. C. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.069 · Cited by 134 · see citing works
Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts
Iqbal, S., & Hood, D. A. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00017.2014 · Cited by 129 · see citing works
The role of Nrf2 in skeletal muscle contractile and mitochondrial function
Crilly, M. J., Tryon, L. D., Erlich, A. T., & Hood, D. A. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00042.2016 · Cited by 94 · see citing works
Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass
Ahn, B., Pharaoh, G. A., Premkumar, P., Huseman, K., Ranjit, R., Kinter, M. T., Szweda, L. I., Kiss, T., Fülöp, G. Á., Tarantini, S., et al. (2018) · Redox Biology · doi:10.1016/j.redox.2018.04.004 · Cited by 94 · see citing works
Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells
Narasimhan, M., Hong, J., Atieno, N., Muthusamy, V. R., Davidson, C. J., Abu-Rmaileh, N., Richardson, R. S., Gomes, A. V., Hoidal, J. R., & Rajasekaran, N. S. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.02.023 · Cited by 87 · see citing works
Tamura, Y., Kitaoka, Y., Matsunaga, Y., Hoshino, D., & Hatta, H. (2015) · The Journal of Physiology · doi:10.1113/jp270093 · Cited by 81 · see citing works
Self-citationWhitman, S. A., Long, M., Wondrak, G. T., Zheng, H., & Zhang, D. D. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.07.015 · Cited by 64 · 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
Kitaoka, 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
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Angulo, J., El Assar, M., Álvarez-Bustos, A., & Rodríguez-Mañas, L. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101513 · Cited by 771 · see citing works
El Assar, M., Álvarez-Bustos, A., Sosa, P., Angulo, J., & Rodríguez-Mañas, L. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158713 · Cited by 371 · 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
Functional, 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
Jacques, M., Landen, S., Sharples, A. P., Garnham, A., Schittenhelm, R., Steele, J., Heikkinen, A., Sillanpää, E., Ollikainen, M., Broatch, J., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115750 · Cited by 23 · see citing works
- Authors
- Kitaoka, Y., Tamura, Y., Takahashi, K., Takeda, K., Takemasa, T., & Hatta, H.
- Affiliations
- Kanagawa University (JP)
- Nippon Sport Science University (JP)
- The University of Tokyo (JP)
- University of Tsukuba (JP)
- Corresponding author
- Kitaoka, Yu
- Venue
- Physiological Reports
- Publisher
- Wiley
- Published
- 2019-02
- Volume
- 7
- Issue
- 3
- Pages
- e13998
- ISSN
- 2051-817X (ISSN-L)
- PMC
- PMC6372533
- OpenAlex
- W2913384044
- Cited by
- 94
- References
- 26
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 17 · 2023: 10 · 2022: 16 · 2021: 13 · 2020: 13 · 2019: 8
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Physiological Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (publishedVersion)
- Terrestrial Environment Research Center (University of Tsukuba) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (18K17941, 26750304)
- Yokohama Academic Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- Nrf2, skeletal muscle aging, mitochondrial oxidative stress, mitochondrial dysfunction, muscle atrophy, Nrf2 knockout mice, 4-hydroxynonenal, protein carbonyls, antioxidant gene expression, mitochondrial respiration, cytochrome c oxidase, Mfn1, mitofusin 2, mitochondrial reactive oxygen species, redox homeostasis
- MeSH terms
- Age Factors, Aging, Aldehydes, Animals, Electron Transport Complex IV, Male, Mice, Inbred C57BL, Mitochondria, Muscle, Mice, Knockout, Oxidative Stress, Muscle, Skeletal, Cell Respiration, GTP Phosphohydrolases, Protein Carbonylation, NF-E2-Related Factor 2, Sarcopenia, Mitochondrial Dynamics
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