Understanding muscle fibre death in Duchenne muscular dystrophy

In this project, Professor Jenny Morgan and her team at University College, London will use a mouse model to investigate the biological process that leads to muscle fibre death in Duchenne muscular dystrophy. They will establish whether a newly identified process is a primary mechanism of cell death and if so, search for potential therapeutic targets that could prevent the loss of muscle fibres.

 

This project is co-funded by three members of the Duchenne Forum – Muscular Dystrophy UK, Duchenne Children’s Trust and The Duchenne Research Fund. The Duchenne Forum is a group of charities working together to accelerate progress in the search for treatments and eventually cures for Duchenne muscular dystrophy.

Duchenne muscular dystrophy is an inherited condition, in which there is a progressive death of muscle fibres. The two main ways in which a cell can die are:

  • Apoptosis, or a cell suicide: the cell organises its own death by digesting itself from the inside. This is a clean way to die, where there is no cell explosion. There is a great deal of knowledge on apoptosis and there are medicines that can prevent it.
  • Necrosis: a disorganised process – the cell rapidly explodes because of external causes (eg cold or heat, physical trauma). The necrotic cell disintegrates, releases its contents and generates a cascade of events that are bad for the whole body. Necrosis is not well understood and is therefore very difficult to control.

In Duchenne muscular dystrophy, muscle fibres die by necrosis, not apoptosis and that is why inhibiting the loss of muscle fibres is so challenging. Our project aims to understand how a muscle fibre dies by necrosis and how this cell death can be prevented.

Inflammation is implicated in the necrosis of dystrophic muscle fibres. We have data supporting our hypothesis that pro-inflammatory cytokines (proteins released by inflammatory cells) elicit cell death by necrosis in muscle cells in culture. We have identified a specific pathway that is implicated in this cell death mechanism. Inhibiting this pathway protects cultured muscle cells from death. We are currently generating mdx mice (a mouse model of Duchenne muscular dystrophy) that are deficient in this pathway. If, as we hypothesise, this genetically-modified mouse is at least partially protected against muscle fibres loss, the next step will be to design a pharmacological agent to inhibit this pathway in mdx mice.

Duchenne muscular dystrophy is characterised by degeneration (necrosis) of muscle fibres. The mechanisms underlying this muscle cell death are poorly understood and therefore need to be investigated in order to generate new therapeutic avenues for Duchenne muscular dystrophy. Proteins released by inflammatory cells are known to be involved in muscle cell death in the mdx mouse model of Duchenne muscular dystrophy. The aim of Professor Morgan and her team is to understand how inflammation induces necrotic death in muscle cells.

In year 2, Professor Morgan’s team have identified proteins that may be involved in the death of muscle fibres that is caused by inflammation.  The researchers are investigating these proteins and how they are involved in cell death in muscle cells in the laboratory. Their findings suggest that a specific signalling pathway is responsible for at least some of the muscle necrosis that occurs in Duchenne muscular dystrophy. To confirm this, the researchers have generated a genetically modified mdx mouse model in which this pathway is blocked. The muscles of these mice are being analysed to determine if they have less necrosis than mdx mice.

Their findings will tell us if the pathway they are investigating might be a new therapeutic target for Duchenne muscular dystrophy.

Data from this project were presented in a poster at the Ninth UK Neuromuscular Research Conference (March 2016) and in a talk by Dr Maximilien Bencze at the London Myology Forum in December 2015.

What are the researchers aiming to do in this project?

The lack of dystrophin in the muscles of boys with Duchenne muscular dystrophy eventually leads to muscle fibres being damaged and dying. Although muscle stem cells can repair this damage and replace lost muscle fibres, the stem cells are eventually exhausted and muscle damage continues. The biological mechanisms that lead to the death of muscle fibres in Duchenne muscular dystrophy are not understood, but recent evidence has suggested that a newly discovered process of regulated cell death may play a role. Such a process that is controlled by the cells themselves  could offer targets for drugs that could prevent muscle fibre death as a potential therapeutic approach for Duchenne muscular dystrophy.

In this project Professor Morgan’s team will use mdx mice – an animal model of Duchenne muscular dystrophy – and human muscle cells grown in the laboratory to confirm whether a regulated process causes muscle fibre death in Duchenne muscular dystrophy. The researchers also aim to stop key molecules in this pathway from working properly to investigate whether this could prolong the life of muscle fibres and slow the decline of muscle function in the mouse model. This could lead to the identification of potential targets for future treatments.

How will the outcomes of the research benefit patients?

This project will increase our understanding of the process that leads to muscle fibre death in Duchenne muscular dystrophy. Specifically, the results will indicate whether regulated processes plays a significant role in fibre death and whether interfering with the pathways leading the cell to die could offer a useful therapeutic approach.

If the results reveal specific new potentially therapeutic compounds, further preclinical testing in animal models will be pursued; this would be a necessary step before performing future clinical trial in humans.

Grant information

Project leader: Professor Jenny Morgan
Location: University College, London
Conditions: Duchenne muscular dystrophy
Duration: three years, starting 2014
Total project cost: £154,065
Official title: Mechanisms of myonecrosis in Duchenne Muscular Dystrophy: can we control the death of muscle fibres?

Further information and links

Download a summary of this research project

Learn more about Duchenne muscular dystrophy and Becker muscular dystrophy

Read about other Duchenne muscular dystrophy and Becker muscular dystrophy research we are funding

Read the latest research news for Duchenne muscular dystrophy

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