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RIPK3-mediated cell death is involved in DUX4-mediated toxicity in facioscapulohumeral dystrophy
Virginie Mariot1, Romain Joubert1,2, Laura Le Gall1
1NIHR Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, London, UK.
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.
Insights
Facioscapulohumeral muscular dystrophy (FSHD) involves DUX4-mediated cell death. Research shows RIPK3-dependent necroptosis contributes to FSHD pathology, suggesting RIPK3 as a therapeutic target.
Area of Science:
- Muscle Diseases
- Cell Death Pathways
- Molecular Biology
Background:
- Facioscapulohumeral muscular dystrophy (FSHD) is linked to DUX4 transcription factor overactivity.
- The precise mechanisms of DUX4-induced muscle cell death, including apoptosis and necrosis, are under investigation.
- FSHD muscle pathology shows necrosis and inflammation, suggesting non-apoptotic cell death pathways may be involved.
Purpose of the Study:
- To investigate the role of necroptosis, a regulated necrosis pathway, in DUX4-mediated cell death.
- To explore the involvement of RIPK3 in DUX4-induced cell death in vitro and in vivo.
Main Methods:
- In vitro studies using myoblasts and myotubes expressing DUX4.
- In vivo experiments utilizing RIPK3 inhibitors and a RIPK3-deficient mouse model.
- Assessment of cell death, gene expression, body and muscle weights, and muscle histology.
Main Results:
- DUX4 expression induced caspase-independent, RIPK3-mediated cell death in muscle cells.
- RIPK3 deficiency in mice improved muscle weight and histology.
- Aberrant DUX4 network gene activation was reduced in RIPK3-deficient animals.
Conclusions:
- RIPK3 plays a significant role in DUX4-mediated cell death in FSHD.
- Targeting RIPK3-dependent necroptosis presents a potential therapeutic strategy for FSHD.
- Further research into RIPK3's role in FSHD is warranted.
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