title: Myogenic-specific ablation of Fgfr1 impairs FGF2-mediated proliferation of satellite cells at the myofiber niche but does not abolish the capacity for muscle regeneration.
abstract: Skeletal muscle satellite cells (SCs) are Pax7(+) myogenic stem cells that reside between the basal lamina and the plasmalemma of the myofiber. In mature muscles, SCs are typically quiescent, but can be activated in response to muscle injury. Depending on the magnitude of tissue trauma, SCs may divide minimally to repair subtle damage within individual myofibers or produce a larger progeny pool that forms new myofibers in cases of overt muscle injury. SC transition through proliferation, differentiation and renewal is governed by the molecular blueprint of the cells as well as by the extracellular milieu at the SC niche. In particular, the role of the fibroblast growth factor (FGF) family in regulating SCs during growth and aging is well recognized. Of the several FGFs shown to affect SCs, FGF1, FGF2, and FGF6 proteins have been documented in adult skeletal muscle. These prototypic paracrine FGFs transmit their mitogenic effect through the FGFRs, which are transmembrane tyrosine kinase receptors. Using the mouse model, we show here that of the four Fgfr genes, only Fgfr1 and Fgfr4 are expressed at relatively high levels in quiescent SCs and their proliferating progeny. To further investigate the role of FGFR1 in adult myogenesis, we have employed a genetic (Cre/loxP) approach for myogenic-specific (MyoD(Cre)-driven) ablation of Fgfr1. Neither muscle histology nor muscle regeneration following cardiotoxin-induced injury were overtly affected in Fgfr1-ablated mice. This suggests that FGFR1 is not obligatory for SC performance in this acute muscle trauma model, where compensatory growth factor/cytokine regulatory cascades may exist. However, the SC mitogenic response to FGF2 is drastically repressed in isolated myofibers prepared from Fgfr1-ablated mice. Collectively, our study indicates that FGFR1 is important for FGF-mediated proliferation of SCs and its mitogenic role is not compensated by FGFR4 that is also highly expressed in SCs.
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
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle WA, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Danoviz
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
keywords: MyoDCre; Pax7; alpha7 integrin; cardiotoxin injury; fibro/adipogenic progenitors; fibroblast growth factor; muscle spindles; satellite cells