FGF6 in Myogenesis ⁎ Anne-Sophie Armand A, Iman Laziz B, Christophe Chanoine B

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Biochimica et Biophysica Acta 1763 (2006) 773–778 www.elsevier.com/locate/bbamcr

Review FGF6 in myogenesis ⁎ Anne-Sophie Armand a, Iman Laziz b, Christophe Chanoine b,

a Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, The Netherlands b UMR 7060 CNRS, Equipe Biologie du Développement et de la Différenciation Neuromusculaire, Centre Universitaire des Saints-Pères, Université René Descartes, F-75270 Paris Cedex 06, France Received 27 April 2006; received in revised form 14 June 2006; accepted 15 June 2006 Available online 22 June 2006

Abstract

Important functions in myogenesis have been proposed for FGF6, a member of the fibroblast growth factor family accumulating almost exclusively in the myogenic lineage. However, the analyses of Fgf6 (−/−) mutant mice gave contradictory results and the role of FGF6 during myogenesis remained largely unclear. Recent reports support the concept that FGF6 has a dual function in muscle regeneration, stimulating myoblast proliferation/migration and muscle differentiation/hypertrophy in a dose-dependent manner. The alternative use of distinct signaling pathways recruiting either FGFR1 or FGFR4 might explain the dual role of FGF6 in myogenesis. A role for FGF6 in the maintenance of a reserve pool of progenitor cells in the skeletal muscle has been also strongly suggested. The aim of this review is to summarize our knowledge on the involvement of FGF6 in myogenesis. © 2006 Elsevier B.V. All rights reserved.

Keywords: FGF6; Myogenesis; Growth factor; Muscle regeneration; Development

1. Introduction disruption of the FGF6 gene have been generated in two different laboratories and skeletal muscle regeneration has Fibroblast growth factors (FGFs) make up a large family of been studied in these FGF6 (−/−) mice, giving rise to polypeptide growth factors that have diverse roles, during contradictory results [7–9]. However, recent reports begin to embryonic development, in regulating cell proliferation, depict the functional involvement of FGF6 in muscle migration and differentiation [1]. In the adult organism, construction, propose a model accounting for the specific FGFs are homeostatic factors and function in tissue repair and role of FGF6 in muscle regeneration [10] and resolve the response to injury [1]. The FGFs transduce their signals to the apparent contradiction of the results from the two FGF6 knock cell through transmembrane tyrosine kinase receptors (FGFRs) out mice [7,8]. The aim of this review is to summarize our for which four distinct genes have been discovered (FGFR1– knowledge on the role of FGF6 in myogenesis. FGFR4) [2]. Among the FGF family members, FGF6 exhibits a restricted expression profile predominantly in the myogenic 1.1. FGF6 gene: structure and expression lineage in adult and developing skeletal muscle [3,4], suggesting that it may be a component of signaling events In mice, the sixth member of the fibroblast growth factor associated with somite formation [5] and the regeneration gene family is composed of three coding exons and encodes a process of the adult muscle [6]. To better understand the putative growth protein of 208 amino acid residues, possessing importance of FGF6 in myogenesis, mice with a homozygous a potential signal peptide and presenting 93.5% sequence similarity with the human FGF6 gene product. The murine Fgf6 gene is located in a region distinct from the Int41 locus and ⁎ Corresponding author. Laboratoire de Biologie du Développement et de la belongs to a linkage group conserved between chromosome 12 Différenciation Neuromusculaire, Centre Universitaire des Saints-Pères, Uni- versité René Descartes, 45 rue des Saints-Pères, F-75720 Paris Cedex 06, in man and chromosome 6 in mouse [11].Comparative France. Fax: +33 1 42 86 21 19. genomics on the mammalian Fgf6 locus revealed that human, E-mail address: [email protected] (C. Chanoine). rat and mouse FGF6 promoters are highly conserved [12].

FGF6 is structurally very similar to the other members of the mice has a biphasic effect, first involving proliferation FGF gene family, and particularly to the Fgf4 gene product. It is characterized by an up-regulation of cyclin D1, followed by expressed as a 4.8 kb transcript in skeletal muscle [13]. Only a an increase of differentiation markers (such as CdkIs, MHCI hybrid growth factor containing features characteristic of both and TnI) and an acceleration of cellular differentiation. FGF4 and FGF6 has been identified in frogs and chickens, The four known FGF receptors, FGFR1 through FGFR4, suggesting that the step of duplication which created FGF4 and share between 55% and 72% identity at the protein level [25]. FGF6 took place with the emergence of mammals. However, in FGF6 induces a transduction signal, preferentially via FGFR1 the trout, a genomic FGF6 clone composed of three exons and FGFR4 as reported by binding studies between the different encoding a putative protein of 206 amino acids and showing FGFs and their FGFRs [26,27]. Mutations in growth factor 64.6 and 63.6% similarity with mouse and human FGF6, receptors expressed in skeletal muscle resulted either in early respectively, and only 46.5% similarity with mouse and human embryonic lethality (FGFR1) [28–30], thereby preventing FGF4 has been isolated [14]. More recently, a cDNA sequence analysis of their functions in muscle cells, or in no apparent encoding sea bass (Dicentrarchus labrax) FGF6 (209 amino phenotypic alterations of muscle development and its main- acids) has been isolated and shows a high sequence identity tenance (FGFR4) [31]. In vivo as well as in vitro, high with other teleost and mammalian FGF6s [15]. concentrations of recombinant FGF6 up-regulated and down- In situ hybridization indicated that Fgf6 expression is regulated the expression of FGFR1 and FGFR4 respectively, restricted to developing skeletal muscle. In mice, Fgf6 supporting the idea that FGF6 is involved in the control of the two transcripts were first detected in embryos at E9.5 and were specific phases of myogenesis, i.e. proliferation and differentia- localized exclusively in the myotomal compartment of the tion, depending on concentration and alternative receptor usage. somites. At E12.5, FGF6 expression was still detected in the In vitro analysis indicated that both FGF6 and FGFR4 were myotome, and also in the region containing the developing uniquely expressed by myofibers and satellite cells, whereas muscles of the body wall. Its expression remains in developing FGFR1 was ubiquitously expressed by myogenic and nonmyo- skeletal muscles up to at least 16.5 days post-conceptus [3,4].In genic cells [23]. FGF receptors have different signaling and the adult rat, FGF6 protein seems selectively expressed in the mitogenic potentials [32,33]. In cultured skeletal muscle satellite fast-type muscles [16]. In the trout, FGF6 transcripts were cells, it has been shown that FGFR1 is required for proliferation detected in fast-twitch and to a lesser extent in slow-twitch and represses differentiation via the ERK1/2 signaling cascade myofibers [14]. The prolonged phase of muscle fiber hyper- [34]. In contrast, in vivo inhibition of FGFR4 signal resulted in an plasia which occurs in trout is accompanied by the lasting arrest of muscle progenitor differentiation [35].Duringmuscle expression of FGF6 up to the adult stage, suggesting that FGF6 regeneration, the pro-differentiation FGFR4 pathway was may participate in the continuous generation of muscle fibers transiently expressed at day 3, commensurate with expression within the myotomal musculature of post-larval animals. FGF6 of MyoD, Myogenin, Myf5, and Pax7. FGFR4 protein is strongly transcripts and protein were also transiently up-regulated after expressed in differentiating myoblasts and newly formed muscle injuries in fast as well as slow muscles [7,17]. During myotubes, suggesting that FGFR4 is likely the key receptor for muscle regeneration, Zhao and Hoffman [18] suggest that FGF6 FGF6 during muscle regeneration [18]. is released from necrotic myofibers, where it is then sequestered by basal laminae. The expression pattern of FGF6 supported the 1.3. Gene knock out mice concept that this particular growth factor could play an important role in myogenesis. The expression pattern of FGF6 supported the concept that this particular growth factor could play an important role in 1.2. FGF6 and its receptors myogenesis. To test this, mice with a homozygous disruption of the FGF6 gene have been generated in two laboratories [7–9]. Numerous FGFs, other than FGF6, are also expressed in The mutant animals were viable, fertile and apparently had skeletal muscle, including FGF2 [19], FGF5 [20] and FGF7 normal skeletal muscle formation. Floss et al. [7], using light [21]. Many of these FGFs, like many other growth factors, have and electronic microscopy as well as immunohistochemical been shown to induce myoblast proliferation in vitro [22]. stainings with antibodies directed against MHC, actin, titin and FGF1, FGF4, FGF2 and FGF6 enhance satellite cell prolifera- desmin, found no significant differences between Fgf6(−/−) tion to a similar degree, whereas FGF5 and FGF7 are ineffective and wild type mice. In contrast, the same authors indicated that [23]. However, as has been also shown for IGF-I, FGF6 is Fgf6(−/−) mutant mice showed a severe regeneration defect involved in proliferation as well as in differentiation of the with fibrosis and myotube degeneration following a freeze- myogenic lineage [6]. Exogenous FGF6 at low or high crush injury. The numbers of MyoD- and myogenin-expressing concentrations respectively stimulates the proliferation of C2 activated satellite cells after injury were significantly reduced myoblasts and delayed differentiation into myotubes or in mutants, presumably due to a lack of activation or increased the expression of muscle cell differentiation markers proliferation of quiescent satellite cells. Interbreeding of Fgf6 [6]. High levels of FGF6 provided by gene transfer, also (−/−) mutants with mdx mice leads to striking dystrophic repressed myogenic determinants in C2C12 myogenic cells and changes in skeletal muscles of double homozygous mice precluded myotube formation [24]. Armand et al. [17] showed characterized by myotube degeneration, the presence of large that a single injection of FGF6 in regenerating soleus of adult numbers of mononuclear cells, and deposition of collagen. A.-S. Armand et al. / Biochimica et Biophysica Acta 1763 (2006) 773–778 775

RNA analysis revealed an up-regulation of MyoD mRNA in the FGF6 cell response. In particular, the up-regulation of mdx but not in Fgf6(−/−)/mdx−/− double mutant mice. FGFR1 and the down-regulation of FGFR4 were observed, In contrast, in the report of Fiore et al. [8], where muscle corroborating the proliferative phenotype of the C2C12 cells degeneration was induced by notexin drug or crush injury, the and their dedifferentiation in the presence of high levels of defect in FGF6 expression apparently did not modify the kinetics FGF6 previously reported [6,17]. These results show that FGF6 of muscle regeneration. Following the breeding Fgf6 −/− mice pushed committed myogenic cells toward a more immature with mdx dystrophin deficient mice, the Fgf6 −/−:mdx and mdx phenotype, resulting in the accumulation of cells with a SP muscles were similar, suggesting that FGF6 is not involved in phenotype and suggesting that FGF6 conditioning could muscle regeneration, i.e., in satellite cell proliferation and fusion, provide a way to expand the pool of immature cells by or that its role is strictly compensated by other factors, possibly myoblast dedifferentiation. other FGFs. To explain the differences observed between the two models of mice lacking FGF6 [36], different hypotheses were 1.5. Muscle differentiation and muscle phenotype suggested. First, variations in the expression of compensating FGF genes in different genetic backgrounds [37] might Histological analysis of regenerating muscle from Fgf6 (−/−) contribute to the difficulties in detecting a major role of FGF6 mice generated by Fiore et al. [8] revealed an earlier detection in muscle regeneration. Another possible explanation for of myotubes following cardiotoxin injection in comparison to differences in the phenotype is the presence or absence of wild type mice [10]. This acceleration of the cellular additional modifier genes or the different design of the targeted differentiation process in regenerating muscles of the mutant mutation, which might lead to considerable differences in the mice was correlated with an increase in the expression of observed phenotypes [38]. In addition, even in a uniform genetic markers of differentiation (CdkIs like p16 and p21, as well as background, stochastic variations in the expression of a calcineurin or myogenin) and of structural proteins (MHCI and regulatory circuit can result in dramatic differences in pheno- slow TnI), along with the up-regulation of calcineurin A typic consequences [39]. phosphatase activity. Calcineurin is a Ca2+/calmodulin- dependent protein serine/threonine phosphatase involved in 1.4. FGF6 and muscle stem cells skeletal muscle growth and differentiation. Calcineurin phosphatase activity is required for the initiation of skeletal muscle Different analyses support the idea that FGF6 and FGF2 cell differentiation in culture [47], for the stimulation of slow could have some common properties in the control of muscle gene promoters, and for slow fiber differentiation both myogenesis [17,40–42]. Targeted transgene delivery of FGF2 in culture and in vivo [48,49]. Similarly, we showed an and FGF6 enhanced muscle repair and FGF gene-treated increase in the number of slow oxidative (type I) myofibers wounds showed on average of a 20-fold increase of regenerat- and a corresponding decrease in the number of fast oxidative ing myotubes expressing the marker CD56 versus untreated (type IIa) myofibers in both regenerating and adult soleus of controls [42] In fact, FGF2 (and FGF4) and more recently Fgf6 (−/−) mice. The rescue experiments by injection of FGF6 have been shown to stimulate the migration of myogenic rhFGF6 confirmed the regulating role of FGF6 on the stem cells in vitro and in vivo [36,43,44]. In this respect [36], calcineurin signaling pathway and indicated that the accumula- indicated that FGF6 deficient mutant myoblasts displayed a tion of both calcineurin and cyclin D1 transcripts was subject decreased migration ability in vivo. The use of dominant- to an opposite dose-dependent regulation by FGF6 [10]. The negative retroviruses for RAS and RAL led these last authors to calcineurin signaling pathway is involved in the nerve-activity- propose that FGFs (FGF2 and FGF6) support the migration of dependent induction and maintenance of fiber-type-specific myoblasts probably through a Ras-/Ral-dependent signaling gene programs [48,50], but our results strongly supported the pathway. In vitro, the reduced ability of FGF2 and FGF6 hypothesis that the lack of FGF6 is responsible for the mutant myoblasts to migrate can be rescued to some extent by precocious and nerve-independent up-regulation of calcineurin the addition of supraphysiological concentrations of either activity in FGF6-deficient mutant mice [10]. This early FGF2 or FGF6, indicating that both growth factors might stimulation of calcineurin triggers the induction of the slow partially compensate for each other. However, Israeli et al. [24] phenotype muscle gene program. Following that, tonic establish a new undescribed link between FGF6 and a innervation takes place, permitting the maintenance of the multidrug resistance gene expressed in stem cells, suggesting slow phenotype detected in myofibers in regenerating and a role for FGF6 in the maintenance of a reserve pool of adult soleus by the induction of a second wave of calcineurin progenitor cells in the skeletal muscle. Indeed using fluores- activation observed from 2 weeks after cardiotoxin injury in cence-activated cell sorting (FACS), the authors showed that regenerating soleus. The transient accumulation of FGF6 the side population (SP) fraction present in the C2C12 line was during soleus regeneration influences both muscle differentia- greatly increased by FGF6 provided by gene transfer. tion and myofiber type switching, acting on both calcineurin Expansion of the pool of cells with SP phenotype was accumulation and calcineurin activity. On the other hand, the correlated with the up-regulation of the mdr1a multidrug overexpression of IGF-II observed in Fgf6 mutant mice [51] resistance gene, which encodes a toxin efflux pump consis- could be substantially involved in the differentiation process tently found in stem cells [45]. With the use of microarray during muscle regeneration of Fgf6 (−/−) mice since it is technology, the same group [46] identified genes involved in known that IGF-II promotes muscle differentiation [52]. 776 A.-S. Armand et al. / Biochimica et Biophysica Acta 1763 (2006) 773–778

1.6. Muscle hypertrophy and protein levels), but not IGF-I and IGF1R, were strongly up-regulated. This observation suggests that, in the absence In regenerating soleus of the Fgf6 (−/−) mice, myofibers of FGF6, the mechanisms leading to myofiber hypertrophy were hypertrophied as compared to wild-type mice [51]. were mediated specifically by an IGF-II/IGF2R signaling IGF-II, one of the members of the insulin-like growth factor pathway distinct from the classic mechanism involving IGF-I family, could play a crucial role in myofiber hypertrophy of and IGF1R previously described as regulating skeletal this mutant mouse. The members of the insulin-like growth muscle hypertrophy. However, although numerous reports factor family (IGF-I and IGF-II) are known to be important have indicated that the overexpression of IGF-I induces in the regulation of myogenesis. These growth factors hypertrophic muscle cells [53], the extent of involvement of enhance both satellite cell proliferation and differentiation IGF-II in the skeletal muscle hypertrophy process remains in vitro [52]. Moreover, IGF-I is able to stimulate muscle unknown, whereas both IGF-I and IGF-II rapidly and hypertrophy (increase in protein content and size of directly induce hypertrophic growth in cultured adult rat myofibers) during muscle regeneration [rev. in 53]. IGFs ventricular cardiomyocytes [57]. Several reports have elicit their effects through binding to the type I IGF receptor indicated that IGF2R signaling occurs through a G-protein- (IGF1R), which is part of a tyrosine kinase signaling coupled pathway that leads to activation of mitogen-activated pathway [54]. The structurally distinct IGF-II receptor protein kinase (MAPK) [58]. Another major player in the (IGF2R)/mannose 6-phosphate receptor lacks tyrosine kinase control of muscle fiber size is myostatin since when the activity [55] and has been shown to be involved in the myostatin gene was disrupted, skeletal muscle mass degradation of IGF-II [56]. In regenerating muscle of the significantly increased, up to three times normal [59].In Fgf6 (−/−) mice, both IGF-II and IGF2R (at the transcript adult myostatin (−/−) mutant mice, IGF-II was also

Fig. 1. Roles of FGF6 in muscle regeneration. Following muscle injury, the transient up-regulation of FGF6 stimulates both the proliferation and migration [36] of the myogenic progenitor cells but also pushes committed myogenic cells toward a more immature phenotype [26,44]. Secondly, the fall of muscle FGF6 regulates, in a dose-dependent manner, both muscle differentiation and muscle phenotype via a nerve-independent signaling calcineurin pathway [10], and myofiber size via an IGF- II/IGF2R pathway [51]. This early stimulation of calcineurin triggers the induction of the slow phenotype muscle gene program. FGF6 up-regulated and down- regulated the expression of FGFR1 and FGFR4 respectively, possibly accounting for biphasic effects of FGF6 on muscle regeneration (i.e. proliferation and differentiation), depending on concentration and alternative receptor usage [6,17]. A.-S. 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