Understanding the molecular causes of myosin-related congenital myopathies

Dr Julien Ochala and his student at King’s College London are aiming to improve our understanding of the molecular causes that underlie two types of congenital myopathies; Laing distal myopathy and Myosin storage myopathy. Importantly, to do this they will generate novel zebrafish models of the conditions. This research will help to direct future research and identify novel therapeutic approaches.

Our project designing in vivo models, has the potential to reveal the molecular and physiological mechanisms of myosin-related myopathies, as well as unravel potential drug targets.

What are the aims of the project?

Myosin storage myopathy and Laing distal myopathy are two types of congenital myopathies caused by mutations in the MYH7 gene. MYH7 produces part of a protein called myosin. Myosin is known as a ‘motor protein’; it generates the mechanical force that is needed for muscles to contract. However, it is unknown how the mutations in MYH7 lead to two different conditions with distinct clinical symptoms and muscle pathologies.

Dr Ochala and his team think that the mutations in each condition affect different parts of the myosin protein and therefore cause different changes to its function. Disrupting myosin function could also trigger different biological pathways, all ultimately leading to muscle damage. In this project they aim to get a better understanding of the faulty myosin and biological pathways that lead to these congenital myopathies.

First the researchers will study myosin from muscle biopsies from people with Laing distal myopathy and myosin storage myopathy. They will use a sensitive technique to measure how different mutations affect the force and power generated by individual myosin molecules. This will tell us how the mutations affect myosin function and if different changes to myosin function result in different types of muscle damage.

Next, Dr Ochala and his team will use genetic tools to make zebrafish models that have some of the mutations that cause Laing distal myopathy and myosin storage myopathy. They will study the structure and function of muscles in these fish. They will also identify cellular pathways in the fish that have been effected by the faulty myosin and could contribute to the muscle damage.

Why is this research important?

The underlying molecular causes of Myosin storage myopathy and Laing distal myopathy are not well understood. This research will increase our knowledge of the causes and improve our understanding of what has gone wrong in the muscle cells of people with these conditions. This is vital to direct future research into potential treatments.

Importantly, there are currently no animal models of these congenital myopathies. The new animal models generated in this project are an important step in the research pathway to increase our understanding of the conditions and to develop and test potential therapies in the future.

How will the outcomes of this research benefit people with myosin-related congenital myopathies?

A better understanding of how faulty myosin leads to Laing distal myopathy and Myosin storage myopathy could allow researchers to design novel therapeutic strategies. For example, disrupting myosin function could trigger a cellular pathway that leads to muscle damage. If identified, a therapeutic option could be to design treatments to block this pathway.

How might this research impact on other neuromuscular conditions?

Myosin, and proteins that it binds to, are important for muscle structure and function. Mutations in myosin genes have been implicated in other myopathies and cardiomyopathies. Therefore, the findings of this research could help to improve the biological understanding of these conditions.

Grant information

Project leader: Dr Julien Ochala
Location: King’s College London
Conditions: Myosin storage myopathy, Laing Distal Myopathy
Duration: 4 years, starting 2017
Total project cost: £112,535
Official title: Phenotype variability in myosin-related congenital myopathies

Further information and links

Find out more about congenital myopathy

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