Abstract Details

DMD is the most frequent inherited human myopathy. Although dystrophin mutations represent the primary cause of DMD, it is the secondary processes involving persistent inflammation that likely exacerbate disease progression. Our group previously described the involvement of the NLRP3 inflammasome as having a major role in this deleterious inflammatory process. Recently, MCC950 was discovered as an extremely potent, selective, small molecule inhibitor of NLRP3 and could thus be promising in muscle diseases with an inflammatory component.

Unravel the therapeutic potential of MCC950, a selective NLRP3 inhibitor, in Duchenne muscular dystrophy(DMD).

Mdx-MCC950 mice exhibited enhanced physical performance versus mdx mice(+40% for wire test,P<0.05; +20% for grip test,P<0.05). In addition, MCC950 reduced significantly inflammation(-45% vs mdx,P<0.05 for IL-1β), oxidative stress(-25% vs mdx,P<0.05 for HNE) and macrophage infiltration(-60% vs mdx,P<0.05 for CD68). Necrosis(~2.4-fold decrease vs mdx,P<0.001), regenerative fibers(~3-fold decrease vs mdx,P<0.001) and small sized myofibers number's were also reduced, proving MCC950 efficacy in reducing the necrosis-regeneration turnover. MCC950 showed also anti-fibrotic properties (Picrosirius staining reduced by ~3.6 fold vs mdx,P<0.05). Finally, the beneficial effects of MCC950 were recapitulated in C2C12 murine myoblasts and human DMD myotubes.

MCC950 improved significantly mice performances, counterbalanced excessive inflammatory and oxidative responses, slowed down the myofibers necrosis-regeneration turnover and reduced muscle fibrosis. These data were replicated with success in C2C12 murine myoblasts and in human myotubes. This molecule could thus offer promising therapeutic prospects for managing DMD or other muscle and inflammatory disorders.