title: Premature proliferative arrest of cricopharyngeal myoblasts in oculo-pharyngeal muscular dystrophy: Therapeutic perspectives of autologous myoblast transplantation.
abstract: Cultures of myoblasts isolated from cricopharyngeal muscles from patients with oculopharyngeal muscular dystrophy (OPMD) have been performed to study the effect of the expanded (GCG)8-13 repeat, located on the poly(A) binding protein nuclear-1 (PABPN1), on satellite cell phenotype. Cell cultures exhibited a reduced myogenicity, as well as a rapid decrease in proliferative lifespan, as compared to controls. The incorporation of BrdU decreased during the proliferative lifespan, due to a progressive accumulation of non-dividing cells. A lower fusion index was also observed, but myoblasts were able to form large myotubes when OPMD cultures were purified, although a rapid loss of myogenicity during successive passages was also observed. Myoblasts isolated from unaffected muscles did not show the defects observed in cricopharyngeal muscle cultures. The PABPN1 was predominantly located in nuclei of myoblasts and in both the nuclei and cytoplasm of myotubes in OPMD cultures. In vivo analysis of OPMD muscles showed that the number of satellite cells was slightly higher than that observed in age matched controls. Mutation of the PABPN1 in OPMD provokes premature senescence in dividing myoblasts, that may be due to intranuclear toxic aggregates. These results suggest that myoblast autografts, isolated from unaffected muscles, and injected into the dystrophic pharyngeal muscles, may be a useful therapeutic strategy to restore muscular function. Its tolerance and feasibility has been preclinically demonstrated in the dog.
authors.affiliation: Inserm U787 Groupe Myologie and Institut de Myologie, Faculté de Médecine Pitié Salpêtrière, Université Paris VI Pierre et Marie Curie, 105, Boulevard de l'Hôpital, 75013 Paris, France. sophie.perie@tnn.ap-hop-paris.fr
authors.forename: Sophie
authors.initials: S
authors.lastname: Périé
authors.forename: Kamel
authors.initials: K
authors.lastname: Mamchaoui
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blot
authors.forename: Belaïd
authors.initials: B
authors.lastname: Bouazza
authors.forename: Lars-Eric
authors.initials: LE
authors.lastname: Thornell
authors.forename: Jean Lacau
authors.initials: JL
authors.lastname: St Guily
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001706:Biopsy; D049109:Cell Proliferation; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D016922:Cellular Senescence; D004247:DNA / Q000378:metabolism; D004285:Dogs; D049631:Esophageal Sphincter, Upper / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D039141:Muscular Dystrophy, Oculopharyngeal / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D010641:Phenotype; D039103:Poly(A)-Binding Protein II / Q000235:genetics* / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology; D014182:Transplantation, Autologous; D018911:Trinucleotide Repeats
chemical_list: D039103:Poly(A)-Binding Protein II; D004247:DNA