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2021-06-24 - Colloque/Présentation - poster - Anglais - page(s)

Nguyen Thuy Hàng , Legrand Alexandre , Decleves Anne-Emilie , Heher Philipp, Banerji Christopher R. S., Zammit Peter S., Tassin Alexandra , "Exploring the Relationship Between DUX4 and Hypoxia-Inducible Factor (HIF1α)" in The 28 th FSHD Society’s annual International Research Congress 2021, 2021

  • Codes CREF : Biochimie (DI3112), Biologie moléculaire (DI3111), Physiologie pathologique (DI3250)
  • Unités de recherche UMONS : Physiologie et réadaptation respiratoire (M117)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)

Abstract(s) :

(Anglais) Studies examining FSHD skeletal muscle molecular networks revealed pathways involved in hypoxic response and oxidative stress to be disturbed, with HIF1α being of particular interest. Our goal is to decipher mechanisms underlying the contribution of the DUX4 - HIF1α crosstalk to muscle dysfunction in FSHD. To this aim, the effect of a sustained HIF1α activation on myogenic differentiation was first investigated in human skeletal muscle cell lines. Hypoxia enhances early myogenic differentiation and fusion of myocytes into multinucleated myotubes. Similar results were obtained in HIF1α gain of function studies using CoCl2. In DUX4-inducible human myoblasts, DUX4 inhibits differentiation and reduces cell viability in a dose dependant manner. In proliferating myoblasts expressing DUX4, the expression of HIF1α and its direct target PDK1 are downregulated at the mRNA and protein level. In myocytes expressing DUX4, no change in HIF1α (mRNA and protein level) and target gene expression (VEGFA and PDK1) was detected but PDK1 protein level was downregulated. In vivo studies on a murine model based on the electroporation of a DUX4 expression vector into mature muscle did not show any significant difference in Hif1A and Pdk1 gene expression at 1, 3, 7 and 14 post-injection. However, at one day post-injection, an increased VegfA expression was observed in the plasmid control group as compared to the saline injected group. This increase seems delayed in the DUX4 group. In conclusion, the HIF1α pathway is modulated upon DUX4 expression but these changes are dependent on the differentiation stage of muscle cells. Moreover, DUX4 induction and HIF1α sustained activation differentially impact the myogenic process.