Hitting Duchenne muscular dystrophy With a One-Two Punch: a Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in mdx Mice

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder which is caused by the lack of dystrophin, a structural sub-sarcolemmal protein whose absence interrupts the mechanical connection between the sarcomeres and the extracellular matrix. This in turn triggers a complex series of pathological events, amongst which are continuous events of fibers degeneration/regeneration coupled to chronic inflammation, that eventually lead to muscle wasting and fibro-fatty replacement. As of today, no resolutive cure is available for DMD patients. In this study we used dystrophic mdx mice to evaluate the efficacy of a dual MAO-B/SSAO inhibitor, PXS-5131, in reducing inflammation and fibrosis and improving muscle function. We found that a one-month treatment starting at three months of age was able to decrease ROS production, fibrosis, and inflammatory infiltrate in the tibialis anterior and diaphragm muscles. Importantly, we also observed a marked improvement in the capacity of the gastrocnemius muscle to maintain its force when challenged with eccentric contractions, a parameter that is severely affected in dystrophic muscles. Upon performing a bulk RNA-seq analysis, we found that treated muscles showed a reduction in the expression of genes linked to the immune system. We also studied the effect of prolonged treatment in older dystrophic mice, and found that a three-month administration of PXS-5131 was able to greatly reduce the progression of fibrosis not only in the diaphragm but also in the heart. Taken together, these results suggest that PXS-5131 is an effective inhibitor of fibrosis and inflammation in dystrophic muscles, a finding that could open a new therapeutic avenue for DMD patients.