Intact satellite cells lead to remarkable protection against Smn gene defect in differentiated skeletal muscle.
Deletion of murine Smn exon 7, the most frequent mutation found in spinal muscular atrophy, has been directed to either both satellite cells, the muscle progenitor cells and fused myotubes, or fused myotubes only. When satellite cells were mutated, mutant mice develop severe myopathic process, progressive motor paralysis, and early death at 1 mo of age (severe mutant). Impaired muscle regeneration of severe mutants correlated with defect of myogenic precursor cells both in vitro and in vivo. In contrast, when satellite cells remained intact, mutant mice develop similar myopathic process but exhibit mild phenotype with median survival of 8 mo and motor performance similar to that of controls (mild mutant). High proportion of regenerating myofibers expressing SMN was observed in mild mutants compensating for progressive loss of mature myofibers within the first 6 mo of age. Then, in spite of normal contractile properties of myofibers, mild mutants develop reduction of muscle force and mass. Progressive decline of muscle regeneration process was no more able to counterbalance muscle degeneration leading to dramatic loss of myofibers. These data indicate that intact satellite cells remarkably improve the survival and motor performance of mutant mice suffering from chronic myopathy, and suggest a limited potential of satellite cells to regenerate skeletal muscle.
Laboratoire de Neurogénétique Moléculaire, INSERM, Université d'Evry, GENOPOLE, Evry, France.
Sophie
S
Nicole
Benedicte
B
Desforges
Gaelle
G
Millet
Jeanne
J
Lesbordes
Carmen
C
Cifuentes-Diaz
Dora
D
Vertes
My Linh
ML
Cao
Fabienne
F
De Backer
Laetitia
L
Languille
Natacha
N
Roblot
Vandana
V
Joshi
Jean-Marie
JM
Gillis
Judith
J
Melki
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D009154:Mutation / Q000235:genetics; D009336:Necrosis; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D016601:RNA-Binding Proteins; D012038:Regeneration / Q000235:genetics*; D055532:SMN Complex Proteins; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins