Open AccessRIPK3‐mediated cell death is involved in DUX4‐mediated toxicity in facioscapulohumeral dystrophy
Author(s) -
Mariot Virginie,
Joubert Romain,
Le Gall Laura,
Sidlauskaite Eva,
Hourde Christophe,
Duddy William,
Voit Thomas,
Bencze Maximilien,
Dumonceaux Julie
Publication year - 2021
Publication title -
journal of cachexia, sarcopenia and muscle
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.803
H-Index - 66
eISSN - 2190-6009
pISSN - 2190-5991
DOI - 10.1002/jcsm.12813
Subject(s) - necroptosis , programmed cell death , facioscapulohumeral muscular dystrophy , microbiology and biotechnology , caspase , myogenesis , apoptosis , biology , necrosis , myocyte , cancer research , muscular dystrophy , genetics
Background Facioscapulohumeral dystrophy (FSHD) is caused by mutations leading to the aberrant expression of the DUX4 transcription factor in muscles. DUX4 was proposed to induce cell death, but the involvement of different death pathways is still discussed. A possible pro‐apoptotic role of DUX4 was proposed, but as FSHD muscles are characterized by 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 experiments 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.