Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity

E. Teveroni, M. Pellegrino, S. Sacconi, P. Calandra, I. Cascino, S. Farioli-Vecchioli, A. Puma, M. Garibaldi, R. Morosetti, G. Tasca, E. Ricci, C.P. Trevisan, G. Galluzzi, A. Pontecorvi, M. Crescenzi, G. Deidda, F. Moretti

Research output: Contribution to journalArticlepeer-review


Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder that is characterized by extreme variability in symptoms, with females being less severely affected than males and presenting a higher proportion of asymptomatic carriers. The sex-related factors involved in the disease are not known. Here, we have utilized myoblasts isolated from FSHD patients (FSHD myoblasts) to investigate the effect of estrogens on muscle properties. Our results demonstrated that estrogens counteract the differentiation impairment of FSHD myoblasts without affecting cell proliferation or survival. Estrogen effects are mediated by estrogen receptor ? (ER?), which reduces chromatin occupancy and transcriptional activity of double homeobox 4 (DUX4), a protein whose aberrant expression has been implicated in FSHD pathogenesis. During myoblast differentiation, we observed that the levels and activity of DUX4 increased progressively and were associated with its enhanced recruitment in the nucleus. ER? interfered with this recruitment by relocalizing DUX4 in the cytoplasm. This work identifies estrogens as a potential disease modifier that underlie sex-related differences in FSHD by protecting against myoblast differentiation impairments in this disease.
Original languageEnglish
Pages (from-to)1531-1545
Number of pages15
JournalJournal of Clinical Investigation
Issue number4
Publication statusPublished - 2017


  • double homeobox 4 protein
  • estrogen
  • estrogen receptor beta
  • homeodomain protein
  • unclassified drug
  • DUX4 protein, human
  • ESR2 protein, human
  • estradiol
  • Article
  • case report
  • cell differentiation
  • cell nucleus
  • cell proliferation
  • cell survival
  • cellular distribution
  • chromatin
  • controlled study
  • cytoplasm
  • facioscapulohumeral muscular dystrophy
  • female
  • human
  • human cell
  • male
  • myoblast
  • priority journal
  • protein expression
  • cell culture
  • gene expression
  • metabolism
  • pathology
  • physiology
  • protein transport
  • transcription initiation
  • Cell Differentiation
  • Cells, Cultured
  • Estradiol
  • Estrogen Receptor beta
  • Estrogens
  • Gene Expression
  • Homeodomain Proteins
  • Humans
  • Muscular Dystrophy, Facioscapulohumeral
  • Myoblasts
  • Protein Transport
  • Transcriptional Activation


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