title: Expression profile and overexpression outcome indicate a role for βKlotho in skeletal muscle fibro/adipogenesis.
abstract: Regeneration of skeletal muscles is required throughout life to ensure optimal performance. Therefore, a better understanding of the resident cells involved in muscle repair is essential. Muscle repair relies on satellite cells (SCs), the resident myogenic progenitors, but also involves the contribution of interstitial cells including fibro/adipocyte progenitors (FAPs). To elucidate the role of the fibroblast growth factor (FGF) signaling in these two cell populations, we previously analyzed freshly isolated cells for their FGF receptor (FGFR) signature. Transcript analysis of the four Fgfr genes revealed distinct expression profiles for SCs and FAPs, raising the possibility that these two cell types have different FGF-mediated processes. Here, we pursued this hypothesis exploring the role of the Klotho genes, whose products are known to function as FGFR co-receptors for the endocrine FGF subfamily. Isolated SC and FAP populations were analyzed in culture, exhibiting spontaneous myogenic or adipogenic differentiation, respectively. αKlotho expression was not detected in either population. βKlotho expression, while not detected in SCs, was strongly upregulated in FAPs entering adipogenic differentiation, coinciding with expression of a panel of adipogenic genes and preceding the appearance of intracellular lipid droplets. Overexpression of βKlotho in mouse cell line models enhanced adipogenesis in NIH3T3 fibroblasts but had no effect on C2C12 myogenic cells. Our study supports a pro-adipogenic role for βKlotho in skeletal muscle fibro/adipogenesis and calls for further research on involvement of the FGF-FGFR-βKlotho axis in the fibro/adipogenic infiltration associated with functional deterioration of skeletal muscle in aging and muscular dystrophy.
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Phelps
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Stuelsatz
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Zipora
authors.initials: Z
authors.lastname: Yablonka-Reuveni
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D000090265:Klotho Proteins; D066292:Lipid Droplets; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C418622:Klb protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; C496366:Fgfr3 protein, mouse; C496372:Fgfr4 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D000090265:Klotho Proteins
keywords: FAPs; FGF21; PiggyBac transposon; adipogenesis; adipogenic differentiation; fibro/adipocytes; fibroblast growth factor receptor; satellite cells; αKlotho; βKlotho