title: Exercise-stimulated FGF23 promotes exercise performance via controlling the excess reactive oxygen species production and enhancing mitochondrial function in skeletal muscle.
abstract: OBJECTIVE
  Physical exercise induces many adaptive changes in skeletal muscle and the whole body and improves metabolic characteristics. Fibroblast growth-factor 23 (FGF23) is a unique member of the FGF family that acts as a hormone regulating phosphate metabolism, calcitriol concentration, and kidney functions. The role of FGF23 in exercise and skeletal muscle is largely unknown yet.
  
  
  METHODS
  C57BL/6J mice were exercised on a motor treadmill. Mice serum FGF23 levels; FGF23 mRNA expression in various organs including the liver, heart, skeletal muscle tissue, and thyroid; and FGF23 receptor Klotho mRNA expression were examined using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and immunoblotting, respectively, after a single bout of acute exercise (60min), exhaustive exercise, and chronic prolonged exercise (60min every day for one week). C57BL/6J mice were injected with recombinant FGF23 (100mg/kg, twice per day, i.p.) or vehicle control (saline) for 3days, and then the exercise performance, reactive oxygen species (ROS), H2O2 production, and mitochondrial functional biomarkers in muscle (gene expression of sirtuin 1, PPAR-δ, PGC-1α and mitochondrial transcription factor A [TFAM], and citrate synthase activity) were assayed.
  
  
  RESULTS
  Three forms of exercise, acute exercise, exhaustive exercise, and chronic exercise, increased serum FGF23 levels. However, only chronic exercise upregulated FGF23 mRNA and protein expression in skeletal muscle. FGF23 mRNA expression in the heart, liver, and thyroid was not affected. FGF23 protein was mainly located in the cytoplasm in skeletal muscle tissue and the localization of FGF23 was not altered by exercise. Exogenous FGF23 treatment significantly extended the time to exhaustion and reduced the exercise-induced ROS and H2O2 production. FGF23 treatment increased the mRNA level of PPAR-δ and citrate synthase activity, but did not influence the mRNA expression of sirtuin 1, PGC-1α, and TFAM in skeletal muscle.
  
  
  CONCLUSIONS
  These results demonstrate that exercise-stimulated FGF23 promotes exercise performance via controlling the excess ROS production and enhancing mitochondrial function in skeletal muscle, which reveals an entirely novel role of FGF23 in skeletal muscle.
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
authors.forename: Dong-Jie
authors.initials: DJ
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ni
authors.affiliation: Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China. Electronic address: fumingshen@tongji.edu.cn.
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Shen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D000090265:Klotho Proteins; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism*; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D009928:Organ Specificity; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005082:Physical Exertion; D011597:Psychomotor Performance; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D047494:PPAR delta; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002950:Citrate (si)-Synthase; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Exercise; FGF23; Mitochondrial function; PPAR-δ; Skeletal muscle