DMD research

New insights into muscle fibre loss in Duchenne muscular dystrophy

Professor Jenny Morgan and her team at University College London (UCL) have shown that a type of cell death called necroptosis has an important role in Duchenne muscular dystrophy. The study – published today in Nature Communications – helps improve our understanding of muscle fibre loss in Duchenne.

The study was co-funded by three members of the Duchenne Forum – Muscular Dystrophy UK, Duchenne Children’s Trust and The Duchenne Research Fund.

Professor Jenny Morgan who led the study said:
This work of Dr Maximilien Bencze and the team furthers our understanding of the role of necroptosis in Duchenne muscular dystrophy, which may pave the way for new potential therapeutic strategies to prevent muscle fibre loss. We are most grateful for the funding we have received from Muscular Dystrophy UK, Duchenne Children’s Trust and the Duchenne Research Fund that supported our work.

You can read more about its findings on Prof Morgan’s grant summary below:

Morgan- RA3/3042- Understanding muscle cell fibre death in Duchenne muscular dystrophy
End of project report

What did the research show?

Muscle cells in people with Duchenne muscular dystrophy undergo an abnormal type of cell death, which is the basis of the muscle wasting.

There are two types of cell death mechanism: apoptosis and necrosis. An apoptotic cell digests itself and a necrotic cell explodes. In Duchenne muscular dystrophy, muscle fibres die by necrosis. Necrosis was believed to be a disorganized process, but it has been recently discovered that necrotic cells can be finely organized. This organized necrosis is called necroptosis.

Professor Morgan, Dr Bencze and colleagues have investigated the role of necroptosis in Duchenne. When one of the proteins of the necroptosis mechanism was blocked in muscle cells grown in the lab, the cells were more resistant to some toxic treatments, which normally trigger cell death.

The researchers also generated a dystrophic mouse model that is missing this protein; this protected cells from necroptosis. In these mice, muscle cell death and scarring (fibrosis) were decreased, and muscle function was improved. These results demonstrate that necroptosis is an important cell mechanism that is involved in dystrophic muscle damage. Targeting necroptotic cell death could therefore be a therapeutic strategy to counteract muscle loss in people with Duchenne.

The team presented this work at conferences including the UK Neuromuscular Translational Research Conference and the 2017 World Muscle Society meeting, where they won a prize. They also published their findings in the scientific journal, Nature Communications.

Why is this research important and next steps?

This work identifies for the first time necroptosis as a cell death mechanism in muscle. Although basic research such as this is a long way from a treatment, it is important to gain a greater understanding of how muscles are damaged in Duchenne muscular dystrophy. These results show that the proteins involved in this cell death pathway do have a role in the symptoms of Duchenne, but further work is needed to understand the mechanisms behind this. If a suitable molecule was identified to block the cell death mechanism, it could help to reduce the cell death of muscle cells and slow down the development of fibrosis. Such an approach could be used in combination with other treatments aiming to restore dystrophin to the muscle.

Could this research benefit people with other neuromuscular conditions?

It is likely that muscle fibres die by this type of cell death mechanism in other neuromuscular conditions. This would need to be investigated in cell and animal models of these conditions.

Any questions please email us: [email protected]

Published on 9 July 2018

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