A new therapeutic strategy for myotubular myopathy
Cross sections of muscles. Left the normal muscle fibers, in the middle those of a diseased mouse and on the right those of a diseased mouse overexpressing Bin1
March 20, 2019
After identifying amphiphysin 2 as a potential therapeutic target in some congenital myopathies, researchers in Jocelyn Laporte's team at the IGBMC (CNRS/Inserm/Université de Strasbourg) were able to specifically modulate the level of this molecule and to reduce all signs of a severe form of myopathy. These results, published on March 20, 2019, in the journal Science translational medicine, offer new therapeutic perspectives for these myopathies.
Centronuclear myopathies (CNMs) are rare genetic diseases characterized by a very debilitating muscle weakness. Mutations in genes encoding myotubularin (MTM1) or amphiphysin2 (BIN1), key players in membrane recycling and remodeling, are responsible for CNM. The most severe form of centronuclear myopathy is caused by mutations in MTM1 and is called myotubular myopathy. To date, no specific therapy is available.
In this study, Valentina Lionello and Belinda Cowling from Jocelyn Laporte's team demonstrated that overexpression of the BIN1 gene in myopathic mice lacking MTM1 (Mtm1-/y) rescue the clinical and histological signs of the disease and prolonged lifespan.
Once this proof-of-concept was established, the researchers used a viral vector to introduce the human BIN1 gene into young mice. They demonstrated that this post-natal injection was effective in reducing the symptoms of the disease and improving the life span of myopathic mice, validating a potential translational approach.
By analyzing the mechanisms involved in myotubular myopathy in mice and in humans, scientists have found that both MTM1 and BIN1 control the adhesion between muscle cells and the location of integrins, which are the mediators of cell adhesion. Alterations in this pathway in Mtm1-/y mice could explain the altered shape and size of muscle fibers, which are the main characteristics of centronuclear myopathy. Overexpression of BIN1 restored integrin function and rescued the integrity of muscle fibers.
BIN1 modulation therefore potentially represents a new therapeutic approach for myotubular myopathies. As myotubularins and BIN1 are also involved in neuropathies and neurodegenerative diseases respectively, these results suggest a broader application for this therapeutic approach.
This study was funded by the National Research Agency (ANR) and the Myotubular Trust and Sparks the Children's Medical research Charity.