In this study, the researchers found that increasing the level of BIN1 (Amphiphysin 2) rescues myotubular myopathy resulting from a MTM1 defect, in an animal model.

“Amphiphysin 2 modulation rescues myotubular myopathy and prevents focal adhesion defects in mice” Lionello et al. Science Translational Medicine 2019
Centronuclear and myotubular myopathies (CNMs) can be due to defects in several genes, including the MTM1 and BIN1 genes. In the present study, the link between MTM1 and BIN1 was investigated in vitro, in cellular systems and ultimately in an animal model (mice).

BIN1 and MTM1 proteins have been shown to interact in skeletal muscles, suggesting they work together for a normal muscle function. When MTM1 is lacking, patients develop myotubular myopathy. BIN1 level was artificially increased in a mouse model of myotubular myopathy lacking MTM1. Increasing BIN1 improved survival and muscle strength, and also prevented the alteration of the muscle histology and structure.

Based on these results which identified BIN1 as a novel target to potentially cure MTM1-related myopathy, a treatment was validated by injecting mice with viral vectors (AAV) containing the human BIN1 gene. Similarly, the production of human BIN1 in the mice rescued most signs of myotubular myopathy.

In addition, scientists during this study found that MTM1 and BIN1 together control the adhesion between muscle fibers, and more precisely the location of integrins, which make the glue between fibers. This may explain the altered shape and size of muscle fibres, which are the main characteristics of most CNMs (small and rounded muscle fibers).

Overall, this data supports the belief that several genes implicated in CNMs work together to maintain the function of muscle fibers, and importantly, this study also identifies BIN1 modulation as a potential therapeutic approach for myotubular myopathy.

This work was funded by a grant from Myotubular Trust covering both the salary of the PhD student who performed most of it and the experimental running costs.  Please read the press release here.

Figure: Comparison of muscle from a wild-type mouse (left), muscle from the MTM1 deficient myotubular myopathy mouse (center) with small and rounder fibers with less contact (center), and a MTM1 deficient myotubular myopathy mouse in which BIN1 level was increased leading to the normalization of muscle structure.

in vitro – A process performed or taking place in a test tube, culture dish, or elsewhere outside a living organism
histology – The microscopic structure of tissues
integrins – Proteins involved in the adhesion/glueing of cells to each other