In the first 8 months of their project Prof. Ottenheijm and his team have been analysing the levels of proteins in muscle biopsies from people with nebulin-based nemaline myopathy. These early findings suggest that some pathways involved in protein degradation are significantly more active in the muscles of people with nemaline myopathy compared to healthy muscles. Next the team will study these pathways in more muscle biopsies, as well as analysing more proteins that are involved in the protein break down process. This will generate a better understanding of the biological mechanisms that underlie nemaline myopathy.
In parallel, the researchers are generating new mouse models (mice that lack both nebulin and MuRF1 proteins). MuRF1 is a protein that plays an important role in the break down of proteins in muscles. The new mouse model will allow the researchers to test the specific role of MuRF1 in the development of muscle weakness in nemaline myopathy.
What are the aims of the project?
The most common cause of nemaline myopathy is mutations in the nebulin gene. Nebulin is an important muscle protein that helps our muscles to contract properly. People with nebulin-based nemaline myopathy are deficient in nebulin protein, which causes them to have muscle weakness.
Muscle weakness can also be caused by muscle shrinkage, or atrophy, which is known to occur in people with nebulin-based nemaline myopathy. This project aims to identify an effective therapeutic approach that can reduce muscle atrophy and weakness.
In collaboration with other nemaline myopathy experts, Professor Ottenheijm will investigate a particular process that breaks down proteins inside cells. This degradative process is thought to contribute to muscle atrophy in people with nebulin-based nemaline myopathy.
Professor Ottenheijm and his team will use patient biopsies and a mouse model to study this process. They will inhibit it with drugs and assess what effect this has on the development of muscle atrophy and weakness in the mouse models.
Why is this research important?
Muscle weakness in nebulin-based nemaline myopathy is caused not only by nebulin deficiency but also by muscle atrophy. The mechanisms that underlie atrophy in nebulin-based nemaline myopathy are not well understood. This project will help to address this by investigating a degradative process that occurs inside the muscle and whether this can be therapeutically targeted with inhibitors.
How will the outcomes of this research benefit those with nemaline myopathy?
This research could lead to the development of a treatment that prevents, or at least slows down, muscle atrophy in people with nebulin-based nemaline myopathy. This could also reduce their muscle weakness.
How might this research impact on other neuromuscular conditions?
The degradative process that this project is investigating underlies muscle atrophy in several neuromuscular conditions. If inhibition of this process reduces muscle atrophy and weakness in nebulin-based nemaline myopathy, then this approach might also benefit people with other muscle atrophy-associated conditions.
Grant information
Project leader: Professor Coen Ottenheijm
Institute: VU University Medical Center, Amsterdam
Condition: Nemaline myopathy
Duration: three years, starting 2017
Total cost: £224,517
Official title: Putting the brakes on muscle atrophy in nebulin-based nemaline myopathy
Further information
Read our factsheet on nemaline myopathy
Find out what other nemaline myopathy research projects we are funding
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