DMD TREATMENT: ANIMAL MODELS: P.211Myostatin inhibition and growth factor treatment of pre- and post-disease onset mdx mice does not improve the phenotype coherently

Abstract

Muscular dystrophies are genetic disorders compromising muscular function and leading to muscular wasting. While several clinical trials have been testing safety and efficacy on promising treatments, no cure exists yet. In the past 15 years myostatin, a negative regulator of muscular mass, has been a major focus of treatment development as mice treated with myostatin inhibitors got larger muscles. Clinical trials have, however, not yet demonstrated a significant ameliorating effect of myostatin inhibition in patients with muscular dystrophy. In order to investigate if myostatin inhibition treatment could be improved by concurrently boosting the muscle regeneration with growth factors we treated 4-week (pre-onset) and 8-week (post-onset) old cohorts of the Duchenne muscular dystrophy mouse model, mdx, with myostatin inhibitor alone, with a growth factor cocktail and with the growth factor cocktail alone once a week for 12 weeks, while monitoring the body weight. At the end of treatment, isometric and eccentric force contraction ex vivo in extensor digitorum longus (EDL) and soleus was determined. The muscular mass was generally bigger in the treatment groups receiving myostatin inhibition with and without growth factors, but specific force overall did not improve. Treatment of post-onset mice demonstrated an improvement of muscular stress resistance compared to controls. Overall, there was no significant overall effect of the treatments, regardless of type and age initiated, compared to controls. These findings in the mdx mice, and absence of clinical improvement in human clinical trials, suggest that treating DMD by means of myostatin inhibition should be re-evaluated.