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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2023

Dystrophin myonuclear domain restoration governs treatment efficacy in dystrophic muscle

Adrien Morin
Amalia Stantzou
Olga Petrova
  • Fonction : Auteur
John Hildyard
Thomas Tensorer
  • Fonction : Auteur
Meriem Matouk
Mina Petkova
  • Fonction : Auteur
Tudor Manoliu
Aurélie Goyenvalle
Markus Schuelke
Corinne Laplace-Builhé
Richard Piercy
Luis Garcia
  • Fonction : Auteur
Helge Amthor

Résumé

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 ( Dmd EGFP ), 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.

Dates et versions

hal-04302715 , version 1 (23-11-2023)

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Citer

Adrien Morin, Amalia Stantzou, Olga Petrova, John Hildyard, Thomas 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-04302715⟩
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