title: Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle.
abstract: Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a) expression in skeletal muscle. Supplementation with the anti-oxidant N-acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle-effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP-LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.
authors.affiliation: Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.|PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Misu
authors.affiliation: Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.|Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takayama
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Yoshiro
authors.identifier: http://orcid.org/0000-0002-0559-5889
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Mita
authors.affiliation: Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.|Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.|Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Kiyo-Aki
authors.initials: KA
authors.lastname: Ishii
authors.affiliation: Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.|Division of Natural System, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Chikamoto
authors.affiliation: Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kanamori
authors.affiliation: Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Tajima
authors.affiliation: Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.|Department of Endocrinology and Metabolism, Chengdu First People's Hospital, Chengdu, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.affiliation: Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Yumie
authors.initials: Y
authors.lastname: Takeshita
authors.affiliation: Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.affiliation: Diagnostic R&D, R&D Headquarters, Alfresa Pharma Corporation, Ibaraki, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Diagnostic R&D, R&D Headquarters, Alfresa Pharma Corporation, Ibaraki, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kato
authors.affiliation: Diagnostic R&D, R&D Headquarters, Alfresa Pharma Corporation, Ibaraki, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Matsuyama
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Division of Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kaito
authors.initials: K
authors.lastname: Iwayama
authors.affiliation: Division of Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.affiliation: Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Akazawa
authors.affiliation: Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Faculty of Medicine, Division of Sports Science, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takekoshi
authors.affiliation: Division of Natural System, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan.|Institute of Science and Engineering, Faculty of Natural System, Kanazawa University, Kanazawa, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsugo
authors.affiliation: Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
authors.affiliation: Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takamura
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015444:Exercise; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D010805:Physical Conditioning, Animal; D064797:Physical Conditioning, Human; D010807:Physical Endurance / Q000187:drug effects / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D051149:Selenoprotein P / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D011973:Receptors, LDL; C000621459:SELENOP protein, human; D051149:Selenoprotein P; D025521:Tumor Suppressor Proteins; D055372:AMP-Activated Protein Kinases; D000111:Acetylcysteine