RIPK3-mediated cell death is involved in DUX4-mediated toxicity in facioscapulohumeral dystrophy

Virginie Mariot, Romain Joubert, Laura Le Gall, Eva Sidlauskaite, Christophe Hourdé, William Duddy, Thomas Voit, Maximilien Bencze, Julie Dumonceaux

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Abstract

Background
Facioscapulohumeral dystrophy (FSHD) is caused by mutations leading to the aberrant expression of theDUX4 transcription factor in muscles. DUX4 was proposed to induce cell death, but the involvement of different deathpathways is still discussed. A possible pro-apoptotic role of DUX4 was proposed, but as FSHD muscles are characterizedby necrosis and inflammatory infiltrates, non-apoptotic pathways may be also involved.

Methods
We explored DUX4-mediated cell death by focusing on the role of one regulated necrosis pathway called necroptosis, which is regulated by RIPK3. We investigated the effect of necroptosis on cell death in vitro and in vivo ex-periments using RIPK3 inhibitors and a RIPK3-deficient transgenic mouse model.

Results
We showed in vitro that DUX4 expression causes a caspase-independent and RIPK3-mediated cell death in both myoblasts and myotubes. In vivo, RIPK3-deficient animals present improved body and muscle weights, a reduction of the aberrant activation of the DUX4 network genes, and an improvement of muscle histology.

Conclusions
These results provide evidence for a role of RIPK3 in DUX4-mediated cell death and open new avenues of research.
Original languageEnglish
Number of pages12
JournalJournal of Cachexia, Sarcopenia and Muscle
Early online date22 Oct 2021
DOIs
Publication statusE-pub ahead of print - 22 Oct 2021

Keywords

  • FSHD
  • DUX4
  • Necroptosis
  • Ripk3
  • Facioscapulohumeral dystrophy

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