Journal Article

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

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

2017

Overview

Selenoprotein P is released from the liver and acts through LRP1 in the muscle to contribute to exercise resistance in mouse and man by inhibiting ROS levels via inhibition of AMPK and PGC-1α. Exercise has numerous health-promoting effects in humans 1 ; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly 2 , 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) phosphorylation 9 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 42/41 / 42/89 / 631/443/319/1642 / 64/60 / 692/163/2743/137/773 / 692/308/1426 / 82/1 / 82/16 / Acetylcysteine - pharmacology / AMP-Activated Protein Kinases - metabolism / Animals / Antioxidants - pharmacology / Biomedicine / Cancer Research / Endocrinology / Exercise / Fitness training programs / Gene expression / Genotype & phenotype / Health promotion / Humans / Infectious Diseases / Kinases / letter / Metabolic Diseases / Metabolism / Mice / Mice, Knockout / Molecular Medicine / Muscle Fibers, Skeletal - metabolism / Muscle, Skeletal - metabolism / Musculoskeletal system / Neurosciences / Oxidizing agents / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism / Phosphorylation / Physical Conditioning, Animal / Physical Conditioning, Human / Physical Endurance - drug effects / Physical Endurance - genetics / Physical fitness / Physical training / Proteins / Reactive Oxygen Species - metabolism / Receptors, LDL - metabolism / Science / Selenoprotein P - genetics / Selenoprotein P - metabolism / Tumor Suppressor Proteins - metabolism / Up-Regulation