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.
Highlights
The 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
Our data showed that NLRP3 is produced by mouse myofibres and could play an important role in muscle inflammation
NLRP3 expression is regulated by ApN and miR-711 as well as by Fas-associated protein with death domain (FADD) in murine myotubes We examined whether NLRP3 is regulated by the anti-inflammatory hormone ApN and its mediator miR711
Summary
The 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 low-grade form characterizes obesity-linked metabolic disorders [1, 2]. ApN turned out to be sufficiently powerful to Boursereau et al BMC Biology (2018) 16:33 offset severe inflammation/oxidative stress and muscle damage in dystrophic muscles of mdx mice (a model of DMD). This was demonstrated in our very own mouse model (mdx-ApN), where mdx animals were crossed with transgenic mice overexpressing ApN [9]. ApN deficiency worsened the mdx phenotype, while muscle electrotransfer of the ApN gene reversed inflammation/oxidative stress and disease progression, thereby suggesting a therapeutic potential for ApN in DMD [10]
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