2023Pdm3 March 30 - Abstract 47 Estrogens recover muscle regeneration impaired by the pathogenic gene, DUX4, in orthotopic human xenograft

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy and one of the more frequent hereditary myopathy. The pathology shows a wide range of clinical signs, with modifying factors contributing to this variability. Among these factors, the beneficial activity of estrogen hormones is still controversial. We investigated the effect of the estrogens 17?-estradiol (E2) and the 5?-dihydrotestosterone-derived 3?-androstenediol (3?-diol) on muscle regeneration. To recapitulate human cell hormone sensitivity, we exploited a humanized heterokaryon FSHD mouse model, constituted by engrafting of human primary muscle mesenchymal stroma cells with perivascular cells (PVCs)-like phenotype in surgery-treated murine muscle. Lentiviral expression of the pathogenic FSHD gene, DUX4, in these cells impaired muscle structural and functional recovery. Notably, both hormones counteracted DUX4 activity and rescued structural and functional muscle performance impaired by DUX4 expression. Interestingly, E2 and 3?-diol act differently on muscle recovery by reducing muscle fibrosis and improving muscle differentiation, respectively. These results demonstrate that estrogens recover murine muscle regeneration reduced by DUX4 expression and support the hypothesis of their beneficial activity on human FSHD muscle.