p62/SQSTM1 and Nrf2 are essential for exercise‐mediated enhancement of antioxidant protein expression in oxidative muscle
Abstract
Increased muscle contractile activity, as observed with regular exercise, prevents oxidative stress—induced muscle wasting, at least partially, by improving the antioxidant defense system. Phosphorylated p62/sequestosome1 competitively binds to the Kelch‐like ECH‐associated protein 1, activating nuclear factor erythroid 2—related factor 2 (Nrf2), which stimulates transcription of antioxidant/electrophile responsive elements. However, it remains to be determined if this process is activated by regular exercise in skeletal muscle. Here, we demonstrate that muscle contractile activity increases antioxidants, Nrf2 translocation into nuclei, and Nrf2 DNA‐binding activity in association with increased p62 phosphorylation (Ser351) in mouse oxidative skeletal muscle. Skeletal muscle‐specific loss of Nrf2 [ i.e ., Nrf2 muscle‐specific knockout (mKO) mice] abolished the expression of the Nrf2 target antioxidant gene NAD(P)H‐quinone oxidoreductase 1 (NQO1) in both glycolytic and oxidative muscles but reduced exercise‐mediated increases of antioxidants ( i.e ., copper/zinc superoxide dismutase (SOD) and extracellular SOD only in oxidative muscle. Interestingly, skeletal muscle—specific loss of p62 ( i.e ., p62 mKO mice) also abolished the expression of NQO1 and reduced exercise‐mediated increases of the same antioxidants in soleus muscle. Collectively, these findings indicate that p62 and Nrf2 cooperatively regulate the exercise‐mediated increase of antioxidants in oxidative muscle.—Yamada, M., Iwata, M., Warabi, E., Oishi, H., Lira, V. A., Okutsu, M. p62/SQSTM1 and Nrf2 are essential for exercise‐mediated enhancement of antioxidant protein expression in oxidative muscle. FASEB J. 33, 8022–8032 (2019). www.fasebj.org
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Reduced NFE2L2 abundance in muscle from 6-month-old Mck-Cre;Nox4fl/fl mice was accompanied by decreased G6PD protein and decreased NQO1, and decreased abundance of proteins involved in antioxidant defense including mitochondrial SOD2, PRDX1 to PRDX3, and catalase.
“the reduced NFE2L2 abundance in muscle from 6-month-old Mck-Cre;Nox4fl/fl mice was accompanied by decreased G6PD protein and decreased NQO1, which is exclusively regulated by NFE2L2 in muscle (41), and a decreased abundance in proteins involved in antioxidant defense, including mitochondrial SOD2, PRDX1 to PRDX3, and catalase (Fig. 6E and fig. S9C).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [41]
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- Authors
- Yamada, M., Iwata, M., Warabi, E., Oishi, H., Lira, V. A., & Okutsu, M.
- Affiliations
- Nagoya City University (JP)
- Nihon Fukushi University (JP)
- University of Tsukuba (JP)
- University of Iowa (US)
- Corresponding author
- Okutsu, Mitsuharu
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2019-03-26
- Volume
- 33
- Issue
- 7
- Pages
- 8022-8032
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2923702879
- Cited by
- 63
- References
- 30
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 11 · 2023: 8 · 2022: 7 · 2021: 11 · 2020: 10 · 2019: 1
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Suzuken Memorial Foundation
- Japan Securities Scholarship Foundation
- Nakatomi Foundation
- Uehara Memorial Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- p62, Nrf2, physical activity, antioxidant defense, oxidative stress, NQO1, copper-zinc superoxide dismutase, Keap1, muscle atrophy, soleus muscle, Nrf2 knockout mice
- MeSH terms
- Sequestosome-1 Protein, Kelch-Like ECH-Associated Protein 1, Animals, Cell Nucleus, Cells, Cultured, Cytoplasm, Glycolysis, Male, Mice, Inbred C57BL, Mice, Transgenic, Muscle Contraction, Oxidation-Reduction, Physical Conditioning, Animal, Running, Superoxide Dismutase, Mice, Knockout, Muscle, Skeletal, Muscle Fibers, Skeletal, Hand Strength, Protein Transport, NF-E2-Related Factor 2, Quadriceps Muscle
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