Investigating the role of muscle stem cells in facioscapulohumeral muscular dystrophy

In this PhD studentship, Professor Peter Zammit and his student, Louise Moyle, explored the role that muscle stem cells have in facioscapulohumeral muscular dystrophy (FSH). They delivered the protein thought to cause FSH (DUX4) into muscle stem cells. DUX4 altered the activity of many genes involved in the way that cells communicate. From this, the researchers identified a protein that appears to contribute to FSH pathology. They then tested clinically-approved drugs against this protein in cell models of FSH to begin to develop a potential therapy.

What were the researchers aiming to do?

The role of muscle stem cells is to maintain and repair skeletal muscle. Researchers have been investigating the possibility of using muscle stem cells to develop a treatment for various forms of muscular dystrophy. Many aspects of muscle stem cell behaviour, however, are still not well understood and some major challenges remain. Muscle maintenance and repair by muscle stem cells does not work properly in FSH and it is thought that this may directly contribute to progression of the condition.
FSH is most often caused by deletion of a segment of DNA in a region called D4Z4. D4Z4 consists of a number of repeated sections of DNA. In FSH, the number of repeats in the D4Z4 region is less than in unaffected individuals. The exact function of the repeated section is unknown but deleting some of these repeats causes a protein called DUX4 to be made. DUX4 is a transcription factor, which means it binds to other genes to control their activity. Abnormal functioning of DUX4 could interfere with muscle stem cell function by either activating genes at the wrong levels, time or place, or interfering with the operation of other important genes. Professor Zammit and his student Louise Moyle tested this theory by delivering DUX4 into mouse muscle stem cells. They then assessed the effects of DUX4 on the activity of different genes that affect how cells communicate. This communication is known as cell signalling and there are many different pathways.

What did their research show?

Professor Zammit and Louise Moyle showed that DUX4 affected the activity of several different cell signalling pathways. In collaboration with a group of computational biologists, Professor Zammit used mathematical analysis to generate a map, which illustrated how these different signalling pathways are interlinked in FSH. Comparing this FSH-specific map with a healthy control signalling map revealed that a protein called beta-catenin plays a central role in FSH. These findings were published in the Journal of The Royal Society Interface.

Professor Zammit and Louise Moyle also showed that DUX4 caused an increase in a protein that controls a signalling pathway in mouse muscle stem cells. To get a better understanding of the role of this protein, the researchers artificially increased and decreased its amount in healthy mouse muscle stem cells and found that it affected their normal function. The researchers concluded that this protein/signalling pathway was an important regulator and so could be a possible drug target in FSH.

This led the researchers to search for clinically approved drugs that inhibit the activity of this signalling pathway. They tested several inhibitors in mouse stem cells and muscle cells that originated from a person with FSH and found that one drug in particular was able to improve the ability of the muscle cells to form muscle fibres, suggesting that it could potentially improve muscle quality in FSH. You can read about this research in more detail in this press release.

What are the next steps?

The researchers plan to further investigate the cell signalling pathway that this protein controls, which will help them to identify other possible drug targets. The researchers will also continue to explore the potential therapeutic role of the clinically approved drug they tested in this project, in collaboration with a pharmaceutical company.

How will the outcomes of the research benefit patients?

The findings of this research will help scientists to understand the biological changes that might occur within the cells of people with FSH. This knowledge is important for future research, which could possibly lead to the first treatments for FSH. The researchers did identify a potentially promising drug, which already has clinical approval, but it is important to remember that this research is still in its early stages and a lot more work needs to be done before human trials could be carried out.

Professor Zammit said about the project,

As ever, we would like to thank Muscular Dystrophy UK for their support for this project. Such basic research is central to understanding the mechanisms underlying disease, which will reveal potential therapies. We are excited about having identified just such a potential target for FSH and hope that with further work, this can move further towards the clinic. In addition, having completed her training at King’s College London, Dr Moyle is now continuing her research into muscle diseases at University College London.

Grant information

Project Leader: Professor Peter Zammit
Location: King’s College London
Condition: Facioscapulohumeral muscular dystrophy (FSH)
Project length: PhD studentship for 4 years, starting 2010
Total Project Cost: £60,000 – Jointly funded with King’s College London
Official Title: Does perturbed satellite cell function contribute to facioscapulohumeral muscular dystrophy?


For further information

Read more about FSH

Read more about research we are funding into FSH

Read more about research progress in FSH

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