Bone marrow transplantation attenuates the myopathic phenotype of a muscular mouse model of spinal muscular atrophy

¹ Molecular Neurogenetics Laboratory, Inserm, Evry, France; University of Evry, Ervy, France
² Inserm, Hôpital Necker-Enfants Malades, Paris, France
³ Department de Pharmacologie Clinique, Hôpital de la Pitié-Salpêtrière, Paris, France

^* To whom correspondence should be addressed. E-mail: j.melki{at}genopole.inserm.fr.

	Abstract

Bone marrow (BM) transplantation was performed on a muscular mouse model of spinal muscular atrophy which 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 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. Yet, 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 HGF, a growth factor that activates quiescent satellite cells, was found in skeletal muscle of transplanted mutants when compared to non transplanted mutants. Eventually, thanks to the CreloxP 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 BMT. HGF may represent an attractive paracrine mechanism to support this activity.

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