title: FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy.
abstract: Fibroblast growth factor 23 (FGF23) is a hormone released primarily by osteocytes that regulates phosphate and vitamin D metabolism. Recent observational studies in humans suggest that circulating FGF23 is independently associated with cardiac hypertrophy and increased mortality, but it is unknown whether FGF23 can directly alter cardiac function. We found that FGF23 significantly increased cardiomyocyte cell size in vitro, the expression of gene markers of cardiac hypertrophy, and total protein content of cardiac muscle. In addition, FGFR1 and FGFR3 mRNA were the most abundantly expressed FGF receptors in cardiomyocytes, and the coreceptor α-klotho was expressed at very low levels. We tested an animal model of chronic kidney disease (Col4a3(-/-) mice) that has elevated serum FGF23. We found elevations in common hypertrophy gene markers in Col4a3(-/-) hearts compared with wild type but did not observe changes in wall thickness or cell size by week 10. However, the Col4a3(-/-) hearts did show reduced fractional shortening (-17%) and ejection fraction (-11%). Acute exposure of primary cardiomyocytes to FGF23 resulted in elevated intracellular Ca(2+) ([Ca(2+)](i); F/F(o) + 86%) which was blocked by verapamil pretreatment. FGF23 also increased ventricular muscle strip contractility (67%), which was inhibited by FGF receptor antagonism. We hypothesize that although FGF23 can acutely increase [Ca(2+)](i), chronically this may lead to decreases in contractile function or stimulate cardiac hypertrophy, as observed with other stress hormones. In conclusion, FGF23 is a novel bone/heart endocrine factor and may be an important mediator of cardiac Ca(2+) regulation and contractile function during chronic kidney disease.
authors: Muscle Biology Group, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors: Chad D
authors: CD
authors: Touchberry
authors: Troy M
authors: TM
authors: Green
authors: Vladimir
authors: V
authors: Tchikrizov
authors: Jaimee E
authors: JE
authors: Mannix
authors: Tiffany F
authors: TF
authors: Mao
authors: Brandon W
authors: BW
authors: Carney
authors: Magdy
authors: M
authors: Girgis
authors: Robert J
authors: RJ
authors: Vincent
authors: Lori A
authors: LA
authors: Wetmore
authors: Buddhadeb
authors: B
authors: Dawn
authors: Lynda F
authors: LF
authors: Bonewald
authors: Jason R
authors: JR
authors: Stubbs
authors: Michael J
authors: MJ
authors: Wacker
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D024141:Collagen Type IV / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D005966:Glucuronidase / Q000235:genetics; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009394:Nephritis, Hereditary / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D061251:Primary Cell Culture; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; C057112:type IV collagen alpha3 chain; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium