Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription
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 o...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-13405-9 |
| _version_ | 1811251466117054464 |
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| author | Amédée Mollard Cécile Peccate Anne Forand Julie Chassagne Laura Julien Pierre Meunier Zoheir Guesmia Thibaut Marais Marc Bitoun France Piétri-Rouxel Sofia Benkhelifa-Ziyyat Stéphanie Lorain |
| author_facet | Amédée Mollard Cécile Peccate Anne Forand Julie Chassagne Laura Julien Pierre Meunier Zoheir Guesmia Thibaut Marais Marc Bitoun France Piétri-Rouxel Sofia Benkhelifa-Ziyyat Stéphanie Lorain |
| author_sort | Amédée Mollard |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:20:56Z |
| format | Article |
| id | doaj.art-5ed91629937e4299abe5d7e2bb11aa5c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T16:20:56Z |
| publishDate | 2022-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-5ed91629937e4299abe5d7e2bb11aa5c2022-12-22T03:25:34ZengNature PortfolioScientific Reports2045-23222022-06-0112111110.1038/s41598-022-13405-9Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcriptionAmédée Mollard0Cécile Peccate1Anne Forand2Julie Chassagne3Laura Julien4Pierre Meunier5Zoheir Guesmia6Thibaut Marais7Marc Bitoun8France Piétri-Rouxel9Sofia Benkhelifa-Ziyyat10Stéphanie Lorain11Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieSorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en MyologieAbstract 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.https://doi.org/10.1038/s41598-022-13405-9 |
| spellingShingle | Amédée Mollard Cécile Peccate Anne Forand Julie Chassagne Laura Julien Pierre Meunier Zoheir Guesmia Thibaut Marais Marc Bitoun France Piétri-Rouxel Sofia Benkhelifa-Ziyyat Stéphanie Lorain Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription Scientific Reports |
| title | Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription |
| title_full | Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription |
| title_fullStr | Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription |
| title_full_unstemmed | Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription |
| title_short | Muscle regeneration affects Adeno Associated Virus 1 mediated transgene transcription |
| title_sort | muscle regeneration affects adeno associated virus 1 mediated transgene transcription |
| url | https://doi.org/10.1038/s41598-022-13405-9 |
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