Estrogen rescues muscle regeneration impaired by DUX4 in a humanized xenograft mouse model

Estrogen rescues muscle regeneration impaired by DUX4 in a humanized xenograft mouse model

Abstract Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy and one of the most frequent hereditary myopathies. The pathology shows a wide range of clinical signs, with modifying factors contributing to this variability, especially in patients with mild disease. Among t...

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Main Authors: Silvia Maiullari, Giada Mele, Patrizia Calandra, Giorgia di Blasio, Sonia Valentini, Alessio Torcinaro, Isabella Manni, Emanuela Teveroni, Fabio Mancino, Luca Proietti, Fabio Maiullari, Maria Pesavento, Ludovica Giorgini, Sabrina Putti, Roberto Rizzi, Sara Bortolani, Ferdinando Scavizzi, Marcello Raspa, Enzo Ricci, Giulia Piaggio, Cesare Gargioli, Alfredo Pontecorvi, Siro Luvisetto, Massimiliano Mazzone, Giancarlo Deidda, Fabiola Moretti
Format: Article
Language:English
Published: Nature Publishing Group 2025-07-01
Series:Cell Death and Disease
Online Access:https://doi.org/10.1038/s41419-025-07827-2
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Summary:Abstract Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy and one of the most frequent hereditary myopathies. The pathology shows a wide range of clinical signs, with modifying factors contributing to this variability, especially in patients with mild disease. Among these factors, the beneficial activity of estrogen hormones is controversial. We investigated the effect of 17β-estradiol (E2) and the 5α-dihydrotestosterone-derived 3β-androstenediol (3β-diol) on muscle regeneration. To recapitulate human hormone sensitivity, we developed a humanized heterokaryon FSHD mouse model by engrafting human immortalized myoblasts or human primary muscle mesenchymal stromal cells into surgically treated murine muscle. Inducible lentiviral expression of the pathogenic FSHD gene, DUX4, in human cells impaired the structural and functional recovery of murine muscle, providing a humanized mouse model of DUX4-mediated pathogenicity and proving that the biological effect of DUX4 spreads across the neighbouring murine nuclei. Both hormones counteracted DUX4 transcriptional activity and rescued structural and functional muscle performance impaired by DUX4 expression, while being inefficient in control grafts. The beneficial activity of estrogen in this heterokaryon model supports the hypothesis that these hormones contribute as a modifying factor in FSHD.
ISSN:2041-4889

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