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

Hirofumi Misu*, Hiroaki Takayama, Yoshiro Saito, Yuichiro Mita, Akihiro Kikuchi, Kiyo Aki Ishii, Keita Chikamoto, Takehiro Kanamori, Natsumi Tajima, Fei Lan, Yumie Takeshita, Masao Honda, Mutsumi Tanaka, Seiji Kato, Naoto Matsuyama, Yuya Yoshioka, Kaito Iwayama, Kumpei Tokuyama, Nobuhiko Akazawa, Seiji MaedaKazuhiro Takekoshi, Seiichi Matsugo, Noriko Noguchi, Shuichi Kaneko, Toshinari Takamura

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)508-516
Number of pages9
JournalNature Medicine
Volume23
Issue number4
DOIs
Publication statusPublished - 2017 Apr 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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