Dystrophin myonuclear domain restoration governs treatment efficacy in dystrophic muscle

A. Morin (1) , Amalia Stantzou (1) , Olga N. Petrova (1) , John C.W. Hildyard (2) , T. Tensorer (3) , Meriem Matouk (1) , M.V. Petkova (4, 5) , Isabelle Richard (6, 7) , T. Manoliu (8, 9) , Aurélie Goyenvalle (1, 10) , S. Falcone (11, 12) , Markus Schuelke (4, 5) , C. Laplace-Builhé (8, 9) , R.J. Piercy (2) , Luis Garcia (1, 10) , Helge Amthor (1, 13, 14, 10)

1 END-ICAP - Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées
2 Royal Veterinary College [London]
3 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
4 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
5 BIH - Berlin Institute of Health
6 Généthon
7 IMBI - Immunologie moléculaire et biothérapies innovantes
8 AMMICa - Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse
9 IGR - Institut Gustave Roussy
10 CSM - Centre Scientifique de Monaco
11 Centre de recherche en Myologie – U974 SU-INSERM
12 Institut de Myologie
13 Hôpital Raymond Poincaré (Garches) [GHU AP-HP Université Paris-Saclay]
14 Université Paris-Saclay

Dystrophin is essential for muscle health: its sarcolemmal absence causes the fatal, X-linked condition, Duchenne muscular dystrophy (DMD). However, its normal, spatial organization remains poorly understood, which hinders the interpretation of efficacy of its therapeutic restoration. Using female reporter mice heterozygous for fluorescently tagged dystrophin (DmdEGFP), we here reveal that dystrophin distribution is unexpectedly compartmentalized, being restricted to myonuclear-defined sarcolemmal territories extending ~80 µm, which we called “basal sarcolemmal dystrophin units (BSDUs).” These territories were further specialized at myotendinous junctions, where both Dmd transcripts and dystrophin protein were enriched. Genome-level correction in X-linked muscular dystrophy mice via CRISPR/Cas9 gene editing restored a mosaic of separated dystrophin domains, whereas transcript-level Dmd correction, following treatment with tricyclo-DNA antisense oligonucleotides, restored dystrophin initially at junctions before extending along the entire fiber—with levels ~2% sufficient to moderate the dystrophic process. We conclude that widespread restoration of fiber dystrophin is likely critical for therapeutic success in DMD, perhaps most importantly, at muscle–tendon junctions

Keywords: dystrophin-EGFP; mdx mouse; myotendinous junction; nuclear domain

Domains: Life Sciences [q-bio]

A. Morin, Amalia Stantzou, Olga N. Petrova, John C.W. Hildyard, T. Tensorer, et al.. Dystrophin myonuclear domain restoration governs treatment efficacy in dystrophic muscle. Proceedings of the National Academy of Sciences of the United States of America, 2023, 120 (2), ⟨10.1073/pnas.2206324120⟩. ⟨hal-04122777⟩