title: Bone marrow transplantation attenuates the myopathic phenotype of a muscular mouse model of spinal muscular atrophy.
abstract: Bone marrow (BM) transplantation was performed on a muscular mouse model of spinal muscular atrophy that had been created by mutating the survival of motor neuron gene (Smn) in myofibers only. This model is characterized by a severe myopathy and progressive loss of muscle fibers leading to paralysis. Transplantation of wild-type BM cells following irradiation at a low dose (6 Gy) improved motor capacity (+85%). This correlated with a normalization of myofiber number associated with a higher number of regenerating myofibers (1.6-fold increase) and an activation of CD34 and Pax7 satellite cells. However, BM cells had a very limited capacity to replace or fuse to mutant myofibers (2%). These data suggest that BM transplantation was able to attenuate the myopathic phenotype through an improvement of skeletal muscle regeneration of recipient mutant mice, a process likely mediated by a biological activity of BM-derived cells. This hypothesis was further supported by the capacity of muscle protein extracts from transplanted mutant mice to promote myoblast proliferation in vitro (1.6-fold increase). In addition, a tremendous upregulation of hepatocyte growth factor (HGF), which activates quiescent satellite cells, was found in skeletal muscle of transplanted mutants compared with nontransplanted mutants. Eventually, thanks to the Cre-loxP system, we show that BM-derived muscle cells were strong candidates harboring this biological activity. Taken together, our data suggest that a biological activity is likely involved in muscle regeneration improvement mediated by BM transplantation. HGF may represent an attractive paracrine mechanism to support this activity.
authors.affiliation: Molecular Neurogenetics Laboratory, Institut National de la Santé et de la Recherche Médicale, Inserm, U798, Evry, F-91057 France.
authors.forename: Nouzha
authors.initials: N
authors.lastname: Salah-Mohellibi
authors.forename: Gaelle
authors.initials: G
authors.lastname: Millet
authors.forename: Isabelle
authors.initials: I
authors.lastname: André-Schmutz
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Desforges
authors.forename: Robert
authors.initials: R
authors.lastname: Olaso
authors.forename: Natacha
authors.initials: N
authors.lastname: Roblot
authors.forename: Sabrina
authors.initials: S
authors.lastname: Courageot
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bensimon
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
authors.forename: Judith
authors.initials: J
authors.lastname: Melki
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000379:methods*; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000473:pathology; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology / Q000502:physiology; D009134:Muscular Atrophy, Spinal / Q000473:pathology*; D009135:Muscular Diseases / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D051763:PAX7 Transcription Factor / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D012333:RNA, Messenger; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor