title: Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan uruno@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yagishita
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.affiliation: Division of Biomedical Engineering for Health and Welfare, Tohoku University Graduate School of Biomedical Engineering, Sendai, Miyagi, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kitajima
authors.affiliation: Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Nunomiya
authors.affiliation: Division of Biomedical Engineering for Health and Welfare, Tohoku University Graduate School of Biomedical Engineering, Sendai, Miyagi, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nagatomi
authors.affiliation: School of Public Health, China Medical University, Shenyang, Liaoning, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Biswal
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan uruno@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods; D006003:Glycogen / Q000378:metabolism*; D006004:Glycogen Debranching Enzyme System / Q000235:genetics*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010764:Phosphorylase Kinase / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D006004:Glycogen Debranching Enzyme System; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D006003:Glycogen; D010764:Phosphorylase Kinase