Abolition of the NLRP3 inflammasome improves the dystrophic phenotype in a murine model of DMD
(2017) 22nd International Congress of the World Muscle Society — Location: (France) Saint-Malo (3.October.2017)
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- (en) Assembly of the NLRP3 inflammasome leads to caspase-1 activation and mediates the cleaving and release of several inflammatory cytokines. The NLRP3 inflammasome can amplify inflammatory responses and thus worsen several diseases. Duchenne muscular dystrophy (DMD) is one of the most devastating muscle disease and it is known to harbor a severe inflammation. We have recently shown that NLRP3 was more expressed in skeletal muscle fibers of mdx mice (a murine model of DMD) than in Wild-Type (WT) mice. Adiponectin (ApN) is a hormone known to possess powerful anti-inflammatory effects on skeletal muscle. Interestingly, transgenic mdx mice that overexpress ApN exhibited lower muscle inflammation/damage as well as higher globular muscle force/endurance when compared to regular mdx mice. These beneficial effects of ApN were associated with a reduction in NLRP3 expression in skeletal muscle. In this study, we investigated the effects of the absence of NLRP3 on the dystrophic phenotype by crossing mdx mice with NLRP3-knockout (NLRP3-KO) mice. First, functional in vivo studies (grip test, wire test and treadmill exercise) were performed on 4 groups of mice: WT, NLRP3-KO, mdx and NLRP3-KO-mdx. Compared to WT, mdx mice presented a strong decrease of global force and endurance that was partially restored in NLRP3-KO-mdx mice. In addition, NLRP3-KO-mdx mice also exhibited a significant decrease in muscle damage, oxidative stress and inflammation as well as a reduction in caspase-1 activation, when compared to regular mdx mice. Furthermore, satellite cells obtained from control and DMD subjects were cultured and differentiated into myotubes. We found that NLRP3 basal expression was 3.5-fold higher in DLD myotubes than in control myotubes. This expression was then reduced after ApN treatment. These novel data show that NLRP3 is implicated in DMD where it plays a key pathogenic role, thus opening new therapeutic perspectives to control muscle inflammation and damage
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Boursereau, R., Abou Samra, M., Lecompte, S., Noel, L., & Brichard, S. (2017). Abolition of the NLRP3 inflammasome improves the dystrophic phenotype in a murine model of DMD. Neuromuscular Disorders, 27, S98. https://doi.org/10.1016/j.nmd.2017.06.028 (Original work published 2017)