A recent study has increased understanding of the underlying biology of sporadic inclusion body myositis (sIBM) and identified a potential therapeutic target. Although this research is in relatively early stages, it could help to develop a new treatment.
One of the underlying causes of sIBM is the disruption of a protein called TDP-43. In healthy muscle cells, TDP-43 is found within the nucleus, where it binds to and controls the activity of various genes. However, in muscle cells affected by sIBM, TDP-43 forms clumps in the cytoplasm. This means it is unable to regulate genes in the nucleus and as a result, the muscle degenerates and weakens.
In a previous study, Dr Todd Cohen and his team at UNC Neuroscience Centre, USA, discovered that TDP-43 clumping occurs as a result of acetylation. This is a molecular ‘switch’ that cells use to turn proteins on or off. When they added acetylated TDP-43 to cells grown in a dish, it could not bind properly to the genes in the nucleus and instead accumulated in the cytoplasm.
In this new study, the researchers investigated the effect of acetylated TDP-43 ‘in vivo’ by injecting it into healthy mice. The mouse muscle cells showed multiple features that are seen in human sIBM, including the TDP-43 clumps.
The researchers then investigated a possible way to remove the TDP-43 clumps. They showed that activation of a protein called HSF1 reduced TDP-43 clumping and improved muscle function in lab-grown cells and in mice with sIBM. They were able to activate HSF1 using existing drugs or by genetic methods. They now hope to identify better oral drugs that target HSF1 and have the same anti-clumping effect.
Dr Cohen said in a press release:
Ideally we would give someone with sIBM a drug that boosts these anti-aggregation systems, and the result would be the removal of the TDP-43 aggregates and the eventual recovery of muscle function.
This study was published in the scientific journal Nature Communications.
Get the latest IBM research news
Download our IBM factsheet
Order an IBM alert card