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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

Nature Medicine volume 23, pages 508–516 (2017)Cite this article

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Abstract

Exercise has numerous health-promoting effects in humans1; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly2,3,4. 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)5,6,7 causes exercise resistance through its muscle receptor low-density lipoprotein receptor–related protein 1 (LRP1)8. 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) phosphorylation9 and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a)10 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.

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Figure 1: Deficiency of SeP enhances responsiveness to exercise training in mice.
Figure 2: SeP suppresses ROS-induced AMPK phosphorylation and Ppargc1a gene expression in cultured myotubes through LRP1.
Figure 3: Deficiency of LRP1 abolishes SeP-induced suppression of AMPK phosphorylation during exercise and enhances responsiveness to exercise training in mice.
Figure 4: SeP functions in human muscle cells and predicts ineffectiveness of training in human subjects.

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Acknowledgements

We thank Y. Furuta, M. Wakabayashi, M. Kawamura, Y. Yamashita and A. Hayashi for technical assistance and H. Asakura for advice on statistical analysis. We also thank K.E. Hill and R.F. Burk (Vanderbilt University School of Medicine) for the Sepp1-knockout mice and C.R. Kahn (Joslin Diabetes Center) for the MCK-Cre transgenic mice. This work was supported by JSPS KAKENHI grants 25461334 (H.M.), 25292078 (Y.S.), 16K09740 (H.M.), 26461329 (T.T.) and 26253046 (S. Kaneko), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (H.M.), the Takeda Science Foundation (H.M.), the MEXT-Supported Program for the Strategic Research Foundation at Private Universities in Japan for years 2012–2016 (N.N.) and JST Adaptable and Seamless Technology Transfer Program (A-STEP) grants AS2311400F (H.M., Y.S. and M.T.) and 15im0302407 (H.M., Y.S. and M.T.).

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

    Hirofumi Misu, Hiroaki Takayama, Akihiro Kikuchi, Kiyo-aki Ishii & Toshinari Takamura

  2. PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan

    Hirofumi Misu

  3. Department of System Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

    Hiroaki Takayama, Akihiro Kikuchi, Kiyo-aki Ishii, Keita Chikamoto, Takehiro Kanamori, Natsumi Tajima, Fei Lan, Yumie Takeshita, Masao Honda & Shuichi Kaneko

  4. Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan

    Yoshiro Saito, Yuichiro Mita, Yuya Yoshioka & Noriko Noguchi

  5. Division of Natural System, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan

    Keita Chikamoto & Seiichi Matsugo

  6. Department of Endocrinology and Metabolism, Chengdu First People's Hospital, Chengdu, China

    Fei Lan

  7. Diagnostic R&D, R&D Headquarters, Alfresa Pharma Corporation, Ibaraki, Japan

    Mutsumi Tanaka, Seiji Kato & Naoto Matsuyama

  8. Division of Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

    Kaito Iwayama & Kumpei Tokuyama

  9. Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan

    Nobuhiko Akazawa & Seiji Maeda

  10. Division of Sports Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Kazuhiro Takekoshi

  11. Institute of Science and Engineering, Faculty of Natural System, Kanazawa University, Kanazawa, Japan

    Seiichi Matsugo

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  1. Hirofumi Misu
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Contributions

H.M. and T.T. conceived the study and designed the experiments; H.T., A.K., K. Ishii, K.C., T.K., N.T., F.L., Y.T., M.T., S. Kato, Y.Y., K. Iwayama, N.A. and H.M. conducted the experiments; Y.S., Y.M., M.H., N.M., K. Tokuyama, S. Maeda, K. Takekoshi, S. Matsugo, N.N. and S. Kaneko analyzed the data and provided the discussion; and H.M. wrote the manuscript with input from the other authors.

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Correspondence to Hirofumi Misu or Toshinari Takamura.

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Misu, H., Takayama, H., Saito, Y. et al. 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. Nat Med 23, 508–516 (2017). https://doi.org/10.1038/nm.4295

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