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.
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 language | English |
|---|---|
| Pages (from-to) | 2079-2090 |
| Number of pages | 12 |
| Journal | Journal of Cachexia, Sarcopenia and Muscle |
| Volume | 12 |
| Issue number | 6 |
| Early online date | 22 Oct 2021 |
| DOIs | |
| Publication status | Published (in print/issue) - Dec 2021 |
Bibliographical note
Funding Information:This study was funded by the FSH Society Grant FSHS-22017-7. M.B. is supported by: Association Fran?aise contre les Myopathies (AFM) via TRANSLAMUSCLE (PROJECT 19507 and 22946). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. We thank Michael Kyba for the iC2C12 cells and Peter Jones for the FLeXDUX4 mouse model. We thank Dr V.M. Dixit for the Ripk3 knockout mice. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.41
Funding Information:
This study was funded by the FSH Society Grant FSHS‐22017‐7. M.B. is supported by: Association Française contre les Myopathies (AFM) via TRANSLAMUSCLE (PROJECT 19507 and 22946). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
Publisher Copyright:
© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.
Keywords
- FSHD
- DUX4
- Necroptosis
- Ripk3
- Facioscapulohumeral dystrophy
