Downregulation of the NLRP3 inflammasome by adiponectin rescues Duchenne muscular dystrophy

Abstract

BackgroundThe hormone adiponectin (ApN) exerts powerful anti-inflammatory effects on skeletal muscle and can reverse devastating myopathies, like Duchenne muscular dystrophy (DMD), where inflammation exacerbates disease progression. The NLRP3 inflammasome plays a key role in the inflammation process, and its aberrant activation leads to several inflammatory or immune diseases. Here we investigated the expression of the NLRP inflammasome in skeletal muscle and its contribution to DMD.ResultsWe find that NLRP3 is expressed in skeletal muscle and show that ApN downregulates NLRP3 via its anti-inflammatory mediator, miR-711. This repression occurs both in vitro in C2C12 myotubes and in vivo after either local (via muscle electrotransfer) or systemic (by using transgenic mice) ApN supplementation. To explore the role of the NLRP3 inflammasome in a murine model of DMD, we crossed mdx mice with Nlrp3-knockout mice. In mdx mice, all components of the inflammasome were upregulated in muscle, and the complex was overactivated. By contrast, in mdx mice lacking Nlrp3, there was a reduction in caspase-1 activation, inflammation and oxidative stress in dystrophic muscle, and these mice showed higher global muscle force/endurance than regular mdx mice as well as decreased muscle damage. To investigate the relevance of NLPR3 regulation in a human disease context, we characterized NLRP3 expression in primary cultures of myotubes from DMD subjects and found a threefold increase compared to control subjects. This overexpression was attenuated by ApN or miR-711 mimic treatments.ConclusionsThe NLRP3 inflammasome plays a key pathogenic role in DMD and muscle inflammation, thereby opening new therapeutic perspectives for these and other related disorders.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0501-z) contains supplementary material, which is available to authorized users.

The Effects of a Theacrine-based Supplement on mRNAs Related to Various Metabolic Processes and Sirtuin Activity in vitro

“…While not widely studied in skeletal muscle, Boursereau et al (22) have shown that NLRP3 protein exists in skeletal muscle, and levels are induced through lipopolysaccharide stimulation. A more recent investigation suggests that that angiotensin II increases skeletal muscle NLRP3 in ammasome formation, and these events lead to mitochondrial dysfunction and muscle atrophy (23).…”

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

“…NLRP3 promotes the cleavage of pro-IL-1β and pro-IL-18 leading to their active forms. NLRP3 was up-regulated in mdx mice but was then normalized in mdx-ApN mice, through miR-711 expression [63].…”

“…Moreover, we have recently identified a strong microRNA candidate, mir-711 for mediating the anti-inflammatory action of ApN on mouse and human skeletal muscles [62]. ApN up-regulated the expression of miR-711, which, in turn, also repressed NF-κB as well as the inflammasome complex [62,63]. Eventually, as mentioned earlier, PGC-1α is also a regulator of cellular oxidant-antioxidant homeostasis by stimulating gene expression of several antioxidant enzymes such as superoxide dismutase-2, catalase, and glutathione peroxidase [43].…”

“…Fourth, up-regulation of miR-711, another PGC-1α target gene (Collagen VII alpha-1) [62] could deter inflammation by a double mechanism. Indeed, miR-711 can repress NF-κB and NLRP3 inflammasome activation [63]. NLRP3 promotes the cleavage of pro-IL-1β and pro-IL-18 leading to their active forms.…”

P2X7 purinoceptor as a therapeutic target in muscular dystrophies

“…Several studies demonstrated that chronic muscle inflammation plays a crucial role in the pathogenesis of DMD. Specifically, anti-cytokine therapies or treatments inducing depletion of CD4, CD8 lymphocytes, neutrophils, dendritic cells or macrophages (that are all found to infiltrate necrotic muscle) significantly improved the dystrophic phenotype in vivo [13,[19][20][21][22][23][24][25][26][27]. Muscles of the mdx mouse, the most commonly used model of DMD, contain 20 times more macrophages and 7 times more dendritic cells than is found in healthy individuals [28].…”