Walking down Skeletal Muscle Lane: From Inflammasome to Disease

Figures

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  Figure 1. The nucleotide-binding oligomerization domain like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome complex. The NLRP3 inflammasome is a multiprotein complex regrouping several proteic actors. In basal conditions, NLRP3 is selfrepressed via an internal interaction between its NACHT and LRR domain. ‘S’, ‘P’, and ‘Ub’ symbols on the inactive form of NLRP3 mean SUMOylation (SUMO, Small Ubiquitin-like Modifier proteins), phosphorylation and ubiquitination, respectively. After its priming, several posttranslational modifications take place (1), leading to the removal of this interaction and the binding of NLRP3 to ASC protein, through its PYD domain, and to NEK7 via its LRR domain, and, thus, NLRP3 activation. In turn, procaspase-1 interacts with ASC through its CARD domain (2). Oligomerization (3) triggers the activation of caspase-1 (4) and the processing of pro-IL-1β, pro-IL-18 and Gasdermin D (GSDMD) into their mature forms, thereby triggering inflammatory cytokines release (5) and pyroptosis (6). ASC, apoptosis associated speck like protein containing a caspase recruitment domain; CARD, caspase recruitment domain; LRR, leucine-rich repeats; NACHT, NAIP…

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  Figure 2. NLRP3 inflammasome priming and activation pathway. Activation of the NLRP3 inflammasome signaling pathway requires two signals. The signal ① or priming (left) is triggered by the stimulation of cytokine receptors (TNFR and IL-1R) or TLRs via several activators, such as LPS, DAMPs or PAMPs. This interaction with their respective receptors will then lead to the upregulation of several inflammasome components (NLRP3, pro-IL-1β and pro-IL-18) via the NF-κB pathway as well as to posttranslational modifications of ASC and NLRP3 protein. Signal ② or activation (right) is triggered by numerous PAMPs or DAMPs including virus, crystals, protein aggregates, LPS, bacterial toxins, or ATP, which will, in turn, activate multiple signaling cascades. The latter involves, among others, K+ efflux, ROS production, lysosomal dysfunction, and the release of mitochondrial DNA in the cytosol. These signals lead eventually to the interaction between NLRP3, ASC and pro-caspase-1, allowing the formation of the NLRP3 multiprotein inflammasome complex. Once activated, caspase 1, the head of the canonical activation, cleaves the pro-IL-1β, pro-IL-18 and Gasdermin D (GSDMD) into their mature forms, triggering…

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  Figure 3. NLRP3 inflammasome excessive activation in skeletal muscle diseases. Lymphocytes in blue, macrophages in purple and neuron in pink.

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  Figure 4. NLRP3 priming and activation in metabolic syndrome. Several activators of either priming or NLRP3 complex formation are numbered in red. They include SFA, LPS ①, inflammatory cytokines such as TNFα ②, stress molecules such as ATP ③, ceramides ④ and ROS ⑤, as well as crystals ⑥. By contrast, inhibitory hormonal or metabolic signals are numbered in green: they include adiponectin (1), MUFA (2) or n-3 PUFA (3), or ketone bodies (β-OHB) (4). Adiponectin binds to AdipoR1 (predominantly expressed in skeletal muscle) or to AdipoR2 (predominantly expressed in liver) to activate AMPK or PPAR-α signaling, respectively. MUFA and PUFA activate AMPK and PPAR-γ signaling, respectively. β-OHB is produced by the liver and is used as fuel by other tissues (such as muscle), where it enters via a MCT. β-OHB, β-hydroxybutyrate; MCT, monocarboxylate transporter; MUFA, mono unsaturated fatty acids; PPAR, peroxisome proliferator activated receptor; PUFA, poly unsaturated fat; SFA, saturated fatty acids. Symbols in circles indicate: ‘P’, phosphorylation; ‘+’, activation; and ‘−’, inhibition.

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  Figure 5. NLRP3 activation and interplay between insulin target tissues. In obesity, adipocyte hypertrophy induces cellular stress together with immune cell infiltration, release of inflammatory adipokines and insulin resistance. Once adipose tissue storage capacity is overwhelmed, ectopic lipid deposit occurs in several other tissues including the liver and skeletal muscle, further worsening inflammation and insulin resistance. This leads to NAFLD/NASH in the liver and to myosteatosis in skeletal muscle. NLRP3 plays a crucial role in metainflammation and in the interplay between these three insulin target tissues.

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  Figure 6. NLRP3 inflammasome and diseased skeletal muscle, case of Duchenne muscular dystrophy. This figure summarizes the central role of NLRP3 in dystrophic muscle inflammation, as well as several of its potential inhibitors. Briefly, the dystrophic muscle is characterized by absence of the dystrophin protein and its associated protein complex, which, in normal cells, links the intracellular cytoskeleton to the extracellular matrix, thus preserving the fiber membrane stability and permeability. Simple contraction of the dystrophic muscle causes microtears in the membrane and the subsequent release of intracellular DAMPS, which, in turn, can act in an autoparacrine manner to activate NLRP3 inflammasome in muscle fibers. Activated NLRP3 leads to an extreme release of inflammatory cytokines and DAMPS, thus maintaining and exaggerating the inflammatory response, eventually leading to pyroptosis and muscle degeneration. Rescuing the dystrophic phenotype can be achieved by alleviating muscle inflammation, in part through repression of NLRP3 inflammasome. This action can be accomplished by several factors. Firstly, adiponectin, a pleiotropic adipokine with potent anti-inflammatory effects,…