Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism
Open accessAbstract
Nrf2 (NF-E2-related factor 2) contributes to the maintenance of glucose homeostasis in vivo Nrf2 suppresses blood glucose levels by protecting pancreatic β cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1 knockout (Keap1MuKO) mice that express abundant Nrf2 in their SkM and then examined Nrf2 target gene expression in that tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated and the levels of the glycogen branching enzyme (Gbe1) and muscle-type PhKα subunit (Phka1) mRNAs, along with those of the glycogen branching enzyme (GBE) and the phosphorylase b kinase α subunit (PhKα) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2 inducers promoted Gbe1 and Phka1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 and Phka1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2 induction in SkM increases GBE and PhKα expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Our results also indicate that Nrf2 differentially regulates glycogen metabolism in SkM and the liver.
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Increasing H2O2 in skeletal muscle or the deletion of KEAP1 enhances insulin sensitivity or improves glucose tolerance.
“Similarly, previous studies have shown that increasing H2O2 in skeletal muscle (8) or the deletion of KEAP1 (9) enhances insulin sensitivity or improves glucose tolerance.”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [9]
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- Authors
- Uruno, A., Yagishita, Y., Katsuoka, F., Kitajima, Y., Nunomiya, A., Nagatomi, R., Pi, J., Biswal, S. S., & Yamamoto, M.
- Affiliations
- Tohoku University (JP)
- China Medical University (CN)
- Johns Hopkins University (US)
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2016-06-01
- Volume
- 36
- Issue
- 11
- Pages
- 1655-1672
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC4959318
- OpenAlex
- W2341191268
- Cited by
- 126
- References
- 57
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 8 · 2023: 14 · 2022: 19 · 2021: 11 · 2020: 18 · 2019: 13 · 2018: 15 · 2017: 7 · 2016: 3
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society of the Promotion of Science (JSPS) grants-in-aid for scientific research (90396474)
- The Japanese Foundation for Applied Enzymology
- JSPS grants-in-aid for scientific research (26893008, 24249015)
- Ministry of Education, Science, Sports and Culture grants-in-aid for scientific research on innovative areas
- the Japan Agency for Medical Research and Development (AMED) platform project for supporting in drug discovery and life science research
- AMED
- Naito Foundation
- Takeda Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- Nrf2, skeletal muscle, glycogen metabolism, glucose homeostasis, glycogen branching enzyme, GBE1, muscle glycogen content, glucose uptake, liver glycogen metabolism
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Cells, Cultured, Glycogen, Glycogen Debranching Enzyme System, Liver, Phosphorylase Kinase, Promoter Regions, Genetic, Mice, Knockout, Muscle, Skeletal, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, NF-E2-Related Factor 2, Mice
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