Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription - CRM - Centre de recherche en myologie - U974 Accéder directement au contenu
Article Dans Une Revue Scientific Reports Année : 2022

Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription

Résumé

Abstract Duchenne muscular dystrophy is a severe neuromuscular disease causing a progressive muscle wasting due to mutations in the DMD gene that lead to the absence of dystrophin protein. Adeno-associated virus (AAV)-based therapies aiming to restore dystrophin in muscles, by either exon skipping or microdystrophin expression, are very promising. However, the absence of dystrophin induces cellular perturbations that hinder AAV therapy efficiency. We focused here on the impact of the necrosis-regeneration process leading to nuclear centralization in myofiber, a common feature of human myopathies, on AAV transduction efficiency. We generated centronucleated myofibers by cardiotoxin injection in wild-type muscles prior to AAV injection. Intramuscular injections of AAV1 vectors show that transgene expression was drastically reduced in regenerated muscles, even when the AAV injection occurred 10 months post-regeneration. We show also that AAV genomes were not lost from cardiotoxin regenerated muscle and were properly localised in the myofiber nuclei but were less transcribed leading to muscle transduction defect. A similar defect was observed in muscles of the DMD mouse model mdx . Therefore, the regeneration process per se could participate to the AAV-mediated transduction defect observed in dystrophic muscles which may limit AAV-based therapies.
Fichier principal
Vignette du fichier
41598_2022_Article_13405 mollard.pdf (2.15 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03828271 , version 1 (25-10-2022)

Identifiants

Citer

Amédée Mollard, Cécile Peccate, Anne Forand, Julie Chassagne, Laura Julien, et al.. Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription. Scientific Reports, 2022, 12 (1), pp.9674. ⟨10.1038/s41598-022-13405-9⟩. ⟨hal-03828271⟩
145 Consultations
29 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More