Team 5 from the Institute of Myology Centre of Research, “RNA-repair based therapeutic strategies and skeletal muscle pathophysiology” directed by France Piétri-Rouxel, demonstrated that a minimum level of 40% of dystrophin is necessary both to recover strength and to improve muscle general condition.
How did you obtain these results?
Our team has a long-standing interest in the nNOS protein that binds to dystrophin. Following a preclinical study carried out in Nantes in the GMRD dog, a large animal model of muscular dystrophy, we analysed biopsies expressing increasing percentages of “dystrophin-positive” fibres (2%, 20%, 40%, 65-90%, etc.). The Nantes team first showed at a macroscopic level, that 40% of dystrophin-positive fibres was sufficient for significant recovery of muscle force. We were more interested in events at the molecular level.
What did you analyse?
We examined the level of dystrophin-positive fibres necessary for certain markers to be standardised, particularly the nNOS and iNOS proteins (normally absent but induced during inflammation). In diseased muscle, these two proteins produce NO within the fibre, which is toxic at high levels, especially for the proper functioning of the RyR1 calcium channel. Standardising these markers always occurs at the same percentage of dystrophin-positive fibres: > 40%, regardless of the approach used (molecular biology, immunology or biochemistry). This is totally consistent with the results of the Nantes team on muscle force recovery.
But if there are 40% dystrophin-positive fibres, this means that 60% of fibres are dystrophin negative. Even if dystrophin is not expressed, the correct levels of nNOS, iNOS and RyR1 markers were measured. So we propose that the 40% dystrophin-positive fibres provides an overall positive environment, in which mechanisms subside and the muscle as a whole, is improved.
What is the next step?
We are now trying to explain why there is a threshold effect, while 60% of the fibres are still dystrophin negative. What creates this positive global environment? Is it a widespread decrease in inflammation? Is it due to regulation of the secretome (a dystrophin negative environment leads the cells to secrete certain proteins in large quantities)? We will test these hypotheses over the coming months.
