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

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.