Understanding how DUX4 and PAX7 contribute to muscle weakness in FSHD

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Professor Peter Zammit and his team at King’s College London are investigating how DUX4 causes facioscapulohumeral muscular dystrophy (FSHD), with a focus on how DUX4 affects an important protein called PAX7. This will improve our understanding of what causes muscle weakness and wasting in FSHD, which is key to developing potential treatments.

What are the aims of the project?

The overall aim of this project is to investigate how DUX4 causes the muscle symptoms of FSHD. It will specifically focus on how DUX4 interferes with activity of a protein called PAX7, which is important for controlling muscle maintenance and repair.

Why is this research important?

FSHD is caused by a change in the DNA that leads to the production of a protein called DUX4, which is not normally present in muscle. DUX4 is a transcription factor, so controls the activity of other genes and the proteins made from these genes. DUX4 disrupts the careful balance of proteins within a muscle cell, ultimately leading to muscle weakness and wasting. However, exactly how this happens is not well understood.

An important protein that DUX4 disrupts is PAX7. This is a transcription factor that is key for the regulation of muscle development, growth, maintenance and repair.

Professor Zammit and his team think that understanding how DUX4 functions in general, and particularly how it disrupts the function of PAX7, is central to understanding pathology in FSHD. This project will explore this theory and investigate how DUX4 functions and its interaction with PAX7. This will help to better understand the molecular changes that cause muscle weakness and wasting in FSHD. Some of these changes could potentially be targets for drug development in the future.

What will the researchers do?

Professor Zammit and his team will carry out various experiments to explore the function of DUX4 and the relationship between DUX4 and PAX7. They will initially study muscle cells in the lab to find out which proteins interact with DUX4 and/or PAX7. They will also test to see if DUX4 and PAX7 directly interact with each other.

The researchers will then study some of the DUX4 and PAX7 interacting proteins in a mouse model of FSHD. They will determine if these proteins are disrupted in the mouse muscle and whether they might contribute to muscle weakness.

Finally the team will study DUX4 and PAX7 in induced pluripotent stem cells (iPSC) from people with FSHD. This will allow them to study the proteins in the early stages of muscle growth and repair and examine effects on gene activity and muscle function.

How will the outcomes of this research benefit people with FSHD?

This research will increase our knowledge of the underlying causes of FSHD, which is important for the development of future treatments.

Professor Zammit and his team have previously shown that genes controlled by PAX7 are biomarkers for FSHD. The findings from this project will build on this work and help to improve our knowledge of biomarkers for FSHD.

Grant information

Principal Investigator: Professor Peter Zammit
Institute: King’s College London
Condition: Facioscapulohumeral muscular dystrophy
Duration: Three years
Total cost: £224,210
Official title: DUX4 and PAX7 interaction in FSHD pathology

Further information

If you would like further details about this research project, please contact the MDUK Research Line on 02078034813 or email research@musculardystrophyuk.org

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