title: Alpha sarcoglycan is required for FGF-dependent myogenic progenitor cell proliferation in vitro and in vivo.
abstract: Mice deficient in α-sarcoglycan (Sgca-null mice) develop progressive muscular dystrophy and serve as a model for human limb girdle muscular dystrophy type 2D. Sgca-null mice suffer a more severe myopathy than that of mdx mice, the model for Duchenne muscular dystrophy. This is the opposite of what is observed in humans and the reason for this is unknown. In an attempt to understand the cellular basis of this severe muscular dystrophy, we isolated clonal populations of myogenic progenitor cells (MPCs), the resident postnatal muscle progenitors of dystrophic and wild-type mice. MPCs from Sgca-null mice generated much smaller clones than MPCs from wild-type or mdx dystrophic mice. Impaired proliferation of Sgca-null myogenic precursors was confirmed by single fiber analysis and this difference correlated with Sgca expression during MPC proliferation. In the absence of dystrophin and associated proteins, which are only expressed after differentiation, SGCA complexes with and stabilizes FGFR1. Deficiency of Sgca leads to an absence of FGFR1 expression at the membrane and impaired MPC proliferation in response to bFGF. The low proliferation rate of Sgca-null MPCs was rescued by transduction with Sgca-expressing lentiviral vectors. When transplanted into dystrophic muscle, Sgca-null MPCs exhibited reduced engraftment. The reduced proliferative ability of Sgca-null MPCs explains, at least in part, the severity of this muscular dystrophy and also why wild-type donor progenitor cells engraft efficiently and consequently ameliorate disease.
authors: Laboratory of Translational Cardiomyology, Stem Cell Interdepartmental Institute, KU Leuven, Herestraat 49 O&N1 bus 814, 3000 Leuven, Belgium.
authors: Marco
authors: M
authors: Cassano
authors: Arianna
authors: A
authors: Dellavalle
authors: Francesco Saverio
authors: FS
authors: Tedesco
authors: Mattia
authors: M
authors: Quattrocelli
authors: Stefania
authors: S
authors: Crippa
authors: Flavio
authors: F
authors: Ronzoni
authors: Agnese
authors: A
authors: Salvade
authors: Emanuele
authors: E
authors: Berardi
authors: Yvan
authors: Y
authors: Torrente
authors: Giulio
authors: G
authors: Cossu
authors: Maurilio
authors: M
authors: Sampaolesi
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D058088:Sarcoglycanopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D049031:Sarcoglycans / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D049031:Sarcoglycans; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1