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

*この研究の対応する著者

研究成果: Article査読

96 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)508-516
ページ数9
ジャーナルNature Medicine
23
4
DOI
出版ステータスPublished - 2017 4月 1
外部発表はい

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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