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. 2017 Apr;23(4):508-516. doi: 10.1038/nm.4295. Epub 2017 Feb 27.


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.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Acetylcysteine / pharmacology
  • Animals
  • Antioxidants / pharmacology
  • Exercise
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Mice
  • Mice, Knockout
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • 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*
  • Reactive Oxygen Species / metabolism*
  • Receptors, LDL / metabolism*
  • Selenoprotein P / genetics*
  • Selenoprotein P / metabolism
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation


  • Antioxidants
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Reactive Oxygen Species
  • Receptors, LDL
  • SELENOP protein, human
  • Selenoprotein P
  • Tumor Suppressor Proteins
  • AMP-Activated Protein Kinases
  • Acetylcysteine