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Innate immune receptors in skeletal muscle metabolism
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Innate immune receptors in skeletal muscle metabolism ⁎
Nicolas J. Pillon , Anna Krook Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden
A R T I C L E I N F O
A BS T RAC T
Keywords: Skeletal muscle Metabolism Inflammation Immunometabolism
Recent decades have seen increasing evidence for a role for both innate and adaptive immunity in response to changes in and in the modulation of metabolic status. This new field of immunometabolism builds on evidence for activation of immune-derived signals in metabolically relevant tissues such as adipose tissue, liver, hypothalamus and skeletal muscle. Skeletal muscle is the primary site of dietary glucose disposal and therefore a key player in the development of diabetes, but studies on the role of inflammation in modulating skeletal muscle metabolism and its possible impact on whole body insulin sensitivity are scarce. This review describes the baseline mRNA expression of innate immune receptors (Toll- and NOD-like receptors) in human skeletal muscle and summarizes studies on putative role of these receptors in skeletal muscle in the context of diabetes, obesity and whole body metabolism.
1. Introduction Innate immunity refers to a number of different nonspecific defence mechanisms that respond rapidly, that is immediately or within hours, of a perturbation of body homeostasis such as tissue damage or appearance of antigens due to pathogenic infection. In recent decades increasing evidence for a role for both innate and adaptive immunity in response to changes in metabolic status has been described [1]. The first paradigm shift was in 2003 with the discovery of an increased number of macrophages in the adipose tissue from obese mice and humans (reviewed in [2]). Since then, evidence for activation of immune-derived signals altering metabolism have been described in several metabolically relevant tissues such as liver, hypothalamus and skeletal muscle, and the number of publications on the topic is still growing (Fig. 1). Skeletal muscle is the primary site of post prandial dietary glucose disposal and therefore a key player in the development of whole-body insulin resistance [3]. The molecular mechanisms leading to glucose uptake in skeletal muscle such as the insulin signalling pathways and the regulation of glucose transporters have been extensively studied, but very little is known about whether and how inflammation modulates these processes. This is surprising as skeletal muscle inflammation has been described during exercise, sarcopenia, muscle growth and repair and is a hallmark of several myopathies [4]. The presence of different types of immune responses in these pathophysiological states suggests that inflammation plays wide-ranging roles in skeletal muscle homeostasis [4]. Immune cell numbers within muscles
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are elevated during obesity and T2D and muscle cells in vitro can mount inflammatory responses under metabolic challenges [5–7], but if and how this could play a role in the regulation of whole body metabolism during obesity and diabetes is still unclear. The signals leading to metabolic inflammation in the adipose tissue and liver involve many of the classical innate immune receptors such at surface receptors like Toll-like receptor 4 (TLR4) and intracellular sensors like the NLRP3 inflammasome. This review therefore focuses on the putative role of these innate immune receptors specifically in skeletal muscle metabolism. 2. Innate immune receptor expression in skeletal muscle Data on the expression of immune receptors in skeletal muscle is scarce, and as in every tissue, it is challenging to decipher whether the abundance of a specific mRNA or protein reflects the actual skeletal muscle fibre, or comes from the many other cells residing in the muscle: endothelial, fibroblasts, immune cells… Taking advantage of expression data from several gene arrays (Table 1), we established the baseline mRNA expression levels in human skeletal muscle biopsies, myofibres and primary muscle cells (Fig. 2). All innate immune receptors are detectable in skeletal muscle biopsies, but most of them fall below the median expression of the tissue. Only MYD88, NLRX1, NAIP, TLR4 and NLRC5 are expressed above the median. The expression levels of these receptors could also be dependent on the type of muscle: soleus having more TLR expressing cells than gastrocnemius muscle [8]. Interestingly, when comparing expression levels
Correspondence to: Karolinska Institutet, Department of Physiology and Pharmacology (FYFA), Integrative Physiology, von Eulers väg 4a, IV, SE-171 77 Stockholm, Sweden. E-mail address: [email protected] (N.J. Pillon).
http://dx.doi.org/10.1016/j.yexcr.2017.02.035 Received 30 December 2016; Accepted 20 February 2017 0014-4827/ © 2017 The Authors. Published by Elsevier Inc.
Please cite this article as: Pillon, N.J., Experimental Cell Research (2017), http://dx.doi.org/10.1016/j.yexcr.2017.02.035
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from muscle biopsies as well as isolated muscle fibres and primary myotubes. As a comparison, we extracted data on the mRNA levels of innate immune receptors in blood-derived human macrophages. As expected from professional pathogen-killing cells, macrophages possess large amounts of MYD88, TLR1/2/4 as well as several NLRs. Isolated muscle fibres show a very similar profile to the muscle biopsy with high expression of MYD88, TLR4 and TLR9 but surprisingly show high mRNA expression of NLRC5 and NLRC3. Primary skeletal muscle cells exhibit high expression of MYD88, TLR4 and TLR3 and significant amounts of NOD1 and NAIP. Overall, the relative expression of immune receptors is consistent between biopsies, isolated fibres and muscle cells. Expression levels change in amplitude between the different models, but the most abundant receptors are consistently MYD88, NRLX1, TLR4, NAIP, NOD1, NLRC5 and TLR9, which suggest that there are expressed by muscle cells themselves. However, even lowly expressed receptors may play important roles depending on the context and the presence or absence of their specific ligands or activators. Literature for metabolic studies involving all these receptors was searched in Pubmed, and the following sections summarise current knowledge regarding the immune receptors described in Fig. 2.
Fig. 1. Number of publications linking inflammation, diabetes and obesity. A PubMed query was performed with the R package “RSImed” using the keywords “(Diabetes OR Obesity) AND Inflammation” in association with metabolic tissues. Data is the number of papers published per 100.000 publications since 1995. The arrow is set in 2003, the year where two papers demonstrated an increased number of macrophages in adipose tissue from obese individuals [69,70].
between various tissues, skeletal muscle had the highest expression of TLR9 amongst all tissues and high expression of TLR4 and TLR5 [9]. Macrophages and other immune cells possess large amount of immune receptors, which could be contributing to the expression levels measured in tissues and biopsies. We therefore analysed gene arrays
3. Toll like receptors (TLR) TLRs are transmembrane proteins recognizing selective pathogen components. TLR3, TLR7, TLR9 are localized in the endosomal compartments whereas other TLRs sit at the plasma membrane [10].
Table 1 Datasets used for the analysis of innate immune receptors in skeletal muscle biopsies, cultured muscle cells and blood-derived macrophages. GEO
Sample
Array
Reference
GSE9103
Vastus Lateralis
[71]
GSE59363
Muscle biopsie
GSE43760
Vastus Lateralis
GSE41769
Vastus Lateralis
GSE17503
Paravertebral Muscle & Primary myotubes
GSE77212
Primary myotubes
GSE45819
Skeletal muscle stem cells
GSE44051
Primary myotubes
GSE26145
Primary myotubes
GSE27073
Primary myotubes
GSE50411
Primary myotubes
GSE28392
Single fibres isolated from Vastus Lateralis
GSE48280
MHC-I-positive myofibers
GSE30536
Blood-derived macrophage
GSE56591
Blood-derived macrophage
GSE10856
Blood-derived macrophage
GSE13670
Blood-derived macrophage
GSE16755
Blood-derived macrophage
GSE20484
Blood-derived macrophage
Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.1 ST Array Illumina humanRef-8 v2.0 expression beadchip Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Exon 1.0 ST Array Illumina humanRef-8 v2.0 expression beadchip Illumina HumanHT-12 V4.0 expression beadchip Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array
Whenever possible, arrays were re-analysed from raw data and normalized to allow relative comparison.
2
[72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89]
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Fig. 2. Immune receptor expression in human skeletal muscle. Expression data from human muscle biopsies, isolated myofibres and primary myotubes as well as human blood-derived macrophages was extracted from publicly available gene arrays (Table 1). All biopsies, fibres and cells were from lean, healthy individuals. Only control and untreated conditions were kept to establish the baseline expression levels. Quantile normalization followed by median centring was performed to compare expression between different arrays.
tendency towards increased serum free fatty acids and reduced fasting glycemia [11]. Acute LPS injection (0.025 or 2 mg/kg, 6 h) lowers fasting blood glucose yet does not affect insulin tolerance [17]. But both chronic (100 μg/kg, daily for 4 wk) or acute (1 μg/kg, single dose) LPS injections reduce mitochondrial respiration. Mitochondria isolated from skeletal muscle from LPS-injected mice have reduced respiratory control ratio (RCR), and ADP- and FCCP-stimulated respiration [12,13] which does not fit with the decreased fatty acid oxidation observed in muscle cells in vitro. TLR4 expression is increased in skeletal muscle during high fat feeding or type 2 diabetes [18]. Mice lacking TLR4 have lower fasting glucose levels and reduced expression of lipogenic enzymes in muscle, which might account for their increased accumulation of triglycerides in skeletal muscle [19]. Deletion of TLR4 also confers significant protection in skeletal muscle against hyperlipidaemia-induced insulin resistance [20] as well as insulin resistance induced by hindlimb unloading [21]. In contrast, specific overexpression of TLR4 in skeletal muscle induces mild glucose intolerance and decreases fatty acid oxidation in lean mice [22]. When challenged with a high fat diet, TLR4-muscle-overexpressing mice gain more weight and display impaired insulin and glucose tolerance compared to their littermate controls [22]. This in vivo data suggests that TLR4 has deleterious effects on skeletal muscle metabolism. The canonical ligand for TLR4 is the bacterial factor LPS, but TLR4 has also been implicated in the activation of inflammatory signalling by saturated fatty acids. Studies using pharmacological agents like the TLR4 inhibitor TAK242, or silencing and knockdown strategies show that inhibition of TLR4 prevents some of the deleterious effects
All TLRs signal through MyD88 to the NF-κB transcription factor, although other alternative routes have been described [10]. 3.1. TLR4 The most studied Toll-like receptor in metabolism is TLR4 with more than 10,000 Pubmed hits for “TLR4 AND metabolism”. Its ligand is lipopolysaccharide (LPS), which has been used in both in vitro and in vivo studies to specifically activate the TLR4 pathway. In C2C12 and primary human skeletal muscle cells, acute stimulation with LPS (500 ng/mL, 2 h) modifies substrate preference, increasing glucose uptake and oxidation while decreasing fatty acid oxidation [11]. Acute exposure of C2C12 myotubes to LPS (100 ng/mL, 12 h) also increases mitochondrial respiration [12]. In both C2C12 and human primary myotubes, acute LPS exposure (50 ng/mL, 2 h) results in increased state 4 O respiration and reduced state 3 u respiration [13]. Paradoxically, chronic treatment with LPS (12–24 h) reduces mitochondrial respiration [13], and skeletal muscle cells exposed to LPS (100 ng/mL, 1–24 h) have impaired insulin signalling and insulinstimulated glucose uptake [14,15]. Overall, in vitro data in skeletal muscle cells suggest that TLR4 stimulation switches metabolism towards glycolysis while inhibiting fatty acid oxidation and inducing insulin resistance. This is strikingly similar to the response observed in immune cells, where inflammatory stimuli switches macrophage metabolism towards glycolysis and away from oxidative phosphorylation [16]. The situation in vivo appears more complex. Some in vitro effects are recapitulated in mice injected acutely with LPS, in which there is a 3
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3.4. TLR5
induced by palmitate or stearate. In L6 myotubes, inhibition of TLR4 activity reduces the capacity of palmitate or oleate to induce insulin resistance [15,20]. TLR4 deficiency ameliorates impaired insulin signalling in muscle and reduced insulin-mediated glucose metabolism induced by lipid infusion [23]. Similarly, in whole soleus muscles ex vivo, incubation with palmitate (1 mM, 6 h) impairs insulin-induced glucose uptake in WT mice, but not in TLR4-defective mice [24]. Some of this data may need to be revisited in light of the fact that Fetuin A has been proposed as a necessary co-factor for the activation of TLR4 by fatty acids [25]. Fetuin A is present in serum and experiments performed in the presence or absence of serum in the culture medium might therefore trigger different effects. In addition, possible traces of endotoxins contamination in fatty acid solutions might also conceal some of the true effects of fatty acids on cells in culture.
Mice deficient for TLR5 develop features of the metabolic syndrome with increased fat mass, altered blood lipid profile and insulin resistance, but the contribution of skeletal muscle per se remains to be investigated [38]. In vitro, skeletal muscle cells do not develop an inflammatory response to the TLR5 ligand flagellin alone [31], but no metabolic responses were measured in these cells. 3.5. TLR9 TLR9 is present in idiopathic inflammatory myopathies, mainly on cell infiltrates and on some injured myofibers [39]. TLR9-deficient non-obese diabetic mice have a significantly reduced incidence of diabetes, which seems to be due to a better beta-cell function [40]. Blockade of TLR9 delays autoimmune diabetes decreased IFN-α production and decreased diabetogenic CD8+ T cells [41]. Overall, TLR9 seems to be involved in the development of autoimmune diabetes. Although it is one of the most abundant TLR at the mRNA level in muscle, the putative role of TLR9 in skeletal muscle metabolism is currently unexplored.
3.2. MyD88 MyD88 is a universal adaptor molecule for Toll-like receptor signalling, involved in signal transduction from all TLRs [26]. Similarly to TLR4, high fat diet increases MyD88 in mouse skeletal muscle [27]. MYD88 mRNA is inversely correlated to quadriceps cross sectional area and muscle strength during recovery from hip fracture surgery [28], and studies have suggested MYD88 also plays a role in muscle growth and regeneration [29]. With regard to metabolism, insulin resistance can be induced in mice by 14 days of hindlimb uploading, which mainly, but not exclusively affects skeletal muscle. In this model, insulin resistance estimated with a glucose tolerance test and insulin signalling in muscle was prevented in MyD88-/- mice [30]. But studies are scarce and more work is needed to decipher the role of MyD88 specifically in skeletal muscle metabolism.
3.6. TLR3/7 TLR3 and TLR7 are almost absent in non-inflammatory muscle but significantly increased in inflammatory myopathies, although primarily detected in inflammatory cells infiltrating the tissue [42]. TLR3 is highly expressed in inclusion body myositis/polymyositis and HIVmyopathies, where muscle fibres express TLR3 in close proximity to infiltrating mononuclear cells [43]. TLR3 expression is reduced in primary myotubes cultured from obese insulin resistant subjects compared to cells cultured from obese insulin sensitive subjects [44]. In addition, TLR3-/- mice have normal whole body insulin sensitivity due to elevated insulin secretion, suggesting that TLR3 might plays a more important role in the pancreas comparatively to other tissues [45].
3.3. TLR2 The baseline expression of TLR2 is low in skeletal muscle (Fig. 2), and the NF-κB activation in skeletal muscle cells after TLR2 stimulation is 20-fold lower than the response to TLR4 agonists [31], suggesting that the role of TLR2 might be less important than TLR4. Nevertheless, TLR2 expression is increased in diet-induced obese mice [32], and skeletal muscle cells exposed to palmitate show enhanced TLR2 mRNA levels [33]. In contrast, no difference was observed in muscle biopsies from human volunteers with impaired glucose tolerance vs control subjects [34]. Insulin-induced IRS1 and Akt phosphorylation is reduced in skeletal muscle from high fat fed mice, and treatment with a TLR2 antisense oligonucleotide can partially reverse this insulin resistance [32]. Additionally, TLR2-/- mice are protected from the deleterious effects of a high fat diet as assessed by glucose tolerance and insulin sensitivity, but the metabolic benefits are likely independent from skeletal muscle. Indeed, skeletal muscle from TLR2-/- mice have increased Acox1 and Mcad mRNA, suggesting changes in beta-oxidation, but other genes involved in fatty acid uptake (Cd36, Pgc1a, Lcad) and inflammation (Cd68, F4/80, Mcp1) are unchanged. TLR2-/- mice have similar muscle triacylglycerols and glycogen content as their littermate controls [35] and in whole soleus muscles ex vivo, incubation with palmitate (1 mM, 6 h) impairs insulin-induced glucose uptake in WT mice, but this is not reversed in TLR2-/-muscles [24]. These contradictory data suggests that the regulation of metabolism by TLR2 might involve a cross-talk with other tissues and that skeletal muscle might not be the primary target of TLR2 in the metabolic syndrome. However, exercise-induced activation of MAPKs and c-Jun is reduced in muscle of TLR2-/- mice [36] and TLR2 knockdown diminishes immobilization-induced skeletal muscle inflammation and atrophy [37], suggesting that TLR2 might be involved in the skeletal muscle response to contraction and atrophy.
3.7. Other TLRs Increased TLR1 and decreased TLR6 mRNA has been reported in response to a high fat diet in skeletal muscle from female mice [35], but to date the role of TLR1, TLR8, TLR6 and TLR10 on skeletal muscle metabolism remain to be investigated. 4. NOD-like receptors (NLR) The NLR family includes several members classified in subfamilies according either to their N-terminal effector domain or their phylogenetic relationships [46,47]. They are all intracellular sensors recognizing either pathogen or danger associated molecular patterns (PAMPs and DAMPs), and some of them are involved in the formation of inflammasomes. 4.1. NOD1/2 NOD1/2 are receptors for intracellular pathogens, recognizing bacterial molecules containing D-glutamyl-meso-diaminopimelic acid and peptidoglycans respectively. Activation of NOD2 by muramyl dipeptide (MDP) in L6 skeletal muscle induces inflammation with activation of the NF-κB pathways and stress kinases. This is associated with insulin resistance as MDP reduces insulin-stimulated signalling and glucose uptake [48]. On the contrary, NOD1 ligands, such as iEDAP, FK156, and FK565, have no significant effect on glucose uptake and insulin resistance in L6 skeletal muscle cells [48]. MDP increases ROS production and carbonyls and reduces mitochondrial membrane potential, suggesting that NOD2-mediated insulin resistance could be 4
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therefore surprising to find it so highly expressed in skeletal muscle biopsies and cells. NLRX1 expression is decreased in the liver of mice fed a high fat diet and even further decreased in obese mice when treated with LPS [60]. NLRX1 seems to negatively regulate TLR-NF-κB signalling and therefore have anti-inflammatory effects [61,62], but whether it plays any role in metabolism is yet to be explored.
due to oxidative stress [49]. In vivo, activation of NOD1 induces insulin resistance. NOD1 ligand-challenged mice show a marked reduction in insulin-dependent phosphorylation of AS160 in skeletal muscle [17]. On the contrary, NOD2 ligands only modestly reduced peripheral glucose disposal. NOD2 activation by MDP failed to alter fasting blood glucose or insulin tolerance when assessed by ITT but reduced peripheral glucose utilization measured with a euglycemic hyperinsulinemic clamp. NOD1/2 double knockout mice are protected from high fat dietinduced inflammation, lipid accumulation, and peripheral insulin intolerance [17]. Data from in vivo experiments suggest that NOD1 activation likely targets liver and adipose tissue more directly than skeletal muscle metabolism, while data from in vitro experiments suggest that insulininduced glucose uptake in skeletal muscle cells is more sensitive to NOD2 ligands. More studies are necessary to better characterize this differential effect of NOD1/2 ligands on muscle metabolism.
4.6. NLRPs Skeletal muscle expression of NRLP3 in humans is higher in skeletal muscle biopsies from subjects eating a high-palmitate diet compared to a low-palmitate/high-oleate diet [63]. Two studies pointed out the role of the NLRP3 inflammasome in sensing saturated fatty acids and regulating cell metabolism [64,65]. In Nlrp3−/− mice, insulin-induced phosphorylation of Akt in skeletal muscle tissues is similar or potentiated compared to the littermate controls [64,65]. In vitro, perilipin 2 overexpression in C2C12 cells leads to accumulation of triglycerides and an increased expression of NLRP3 along with an impaired insulin-induced glucose uptake. Silencing of NLRP3 partially reverses perilipin-induced insulin resistance in skeletal muscle cells [66]. NLRP3 inflammasome seems to be also involved in myopathies, as NLRP3 is up-regulated and activated in dysferlin-deficient muscle [67]. Apart from NLRP3 very little is known about the role of the other NLRP molecules in skeletal muscle metabolism.
4.2. CIITA CIITA (Class II Major Histocompatibility Complex Transactivator) is a transcriptional coactivator abundant in human leukocytes. High-fat diet increases CITTA mRNA in adipose tissue, and regulates tissue inflammation [50]. Whole body knockout of CIITA protects non-obesediabetic mice from type-1 diabetes despite infiltration of immune cells in the pancreas [51], but the involvement of CITTA in type 2 diabetes in unexplored. In C2C12 mouse skeletal muscle cells, IFNγ disrupts the expression of genes involved in metabolism and energy expenditure by repressing the expression and activity of SIRT1. These deleterious effects of INFγ are mediated through an induction of CIITA which is recruited to the SIRT1 promoter and promotes down-regulation of SIRT1 transcription [52]. CIITA also represses Pdk4 transcription by directly targeting SIRT1 in a mechanism that involved HDAC4 [53,54]. CIITA is also involved in IFNγ-induced inhibition of myogenesis by binding to and inhibiting myogenin activity [55], suggesting that it can potentially affect many functions in skeletal muscle cells. Yet, data on the possible role of CITTA in regulating expression of metabolic genes is solely based on results from C2C12 cultured cells and need to be confirmed in other models as well as in vivo.
5. Conclusion In comparison to adipose tissue and liver, the study of innate immune receptors in skeletal muscle has been neglected, and the role and possible influence on whole body metabolism of these receptors remains largely unknown. In addition to the expression of the receptors on myocytes, innate immune receptors expressed on resident immune cells could also affect the whole tissue by regulating metabolism through cell-cell communication [4]. For instance, in vitro experiments provide proof of concept that macrophages exposed to fatty acids release cytokines that impact muscle insulin sensitivity [68] and on the other hand that muscle cells have the ability to secrete factors affecting the immune system [5,7]. In the context of a worldwide epidemic of obesity and diabetes and a lack of efficient therapeutic strategies to treat or prevent it, targeting skeletal muscle immunometabolic processes could potentially provide novel strategies to improve insulin sensitivity.
4.3. NAIP NAIP deletions are associated with an early onset and worse outcome in spinal muscular atrophy [56], but no other role in skeletal muscle has been described.
Acknowledgments This work was supported by the Novo Nordisk Foundation Initiative on Immunometabolism (NNF15CC0018346), the Swedish Research Council (2012-1760), the Swedish Diabetes Association (DIA2015-032), the Stockholm County Council (20150326), Diabetes Wellness Network Sweden (783_2015PG) and the Strategic Research Programme in Diabetes at Karolinska Institutet (Swedish Research Council grant No 2009-1068). NJP was supported by a Marie Skłodowska-Curie Fellowship (H2020-MSCA-IF-2015, 704978) and grants from the Lars Hiertas Minne Foundation (FO2015-0507, FO2016-0283).
4.4. NLRCs Infection with Salmonella induces muscle wasting, which can be prevented by colonization of the mice by a specific strain of Escherichia coli (O21:H+). In the presence of this specific E. coli strain, signalling through insulin-like growth factor 1/phosphatidylinositol 3-kinase/ AKT was preserved in skeletal muscle. This effect was mediated through NLRC4 and the production of IGF1 by the adipose tissue, but the study did not address whether NLRC4 in the skeletal muscle was involved [57]. To date, the role of the NLRC receptors in skeletal muscle is unexplored.
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Innate immune receptors in skeletal muscle metabolism ⁎
Nicolas J. Pillon , Anna Krook Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm, Sweden
A R T I C L E I N F O
A BS T RAC T
Keywords: Skeletal muscle Metabolism Inflammation Immunometabolism
Recent decades have seen increasing evidence for a role for both innate and adaptive immunity in response to changes in and in the modulation of metabolic status. This new field of immunometabolism builds on evidence for activation of immune-derived signals in metabolically relevant tissues such as adipose tissue, liver, hypothalamus and skeletal muscle. Skeletal muscle is the primary site of dietary glucose disposal and therefore a key player in the development of diabetes, but studies on the role of inflammation in modulating skeletal muscle metabolism and its possible impact on whole body insulin sensitivity are scarce. This review describes the baseline mRNA expression of innate immune receptors (Toll- and NOD-like receptors) in human skeletal muscle and summarizes studies on putative role of these receptors in skeletal muscle in the context of diabetes, obesity and whole body metabolism.
1. Introduction Innate immunity refers to a number of different nonspecific defence mechanisms that respond rapidly, that is immediately or within hours, of a perturbation of body homeostasis such as tissue damage or appearance of antigens due to pathogenic infection. In recent decades increasing evidence for a role for both innate and adaptive immunity in response to changes in metabolic status has been described [1]. The first paradigm shift was in 2003 with the discovery of an increased number of macrophages in the adipose tissue from obese mice and humans (reviewed in [2]). Since then, evidence for activation of immune-derived signals altering metabolism have been described in several metabolically relevant tissues such as liver, hypothalamus and skeletal muscle, and the number of publications on the topic is still growing (Fig. 1). Skeletal muscle is the primary site of post prandial dietary glucose disposal and therefore a key player in the development of whole-body insulin resistance [3]. The molecular mechanisms leading to glucose uptake in skeletal muscle such as the insulin signalling pathways and the regulation of glucose transporters have been extensively studied, but very little is known about whether and how inflammation modulates these processes. This is surprising as skeletal muscle inflammation has been described during exercise, sarcopenia, muscle growth and repair and is a hallmark of several myopathies [4]. The presence of different types of immune responses in these pathophysiological states suggests that inflammation plays wide-ranging roles in skeletal muscle homeostasis [4]. Immune cell numbers within muscles
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are elevated during obesity and T2D and muscle cells in vitro can mount inflammatory responses under metabolic challenges [5–7], but if and how this could play a role in the regulation of whole body metabolism during obesity and diabetes is still unclear. The signals leading to metabolic inflammation in the adipose tissue and liver involve many of the classical innate immune receptors such at surface receptors like Toll-like receptor 4 (TLR4) and intracellular sensors like the NLRP3 inflammasome. This review therefore focuses on the putative role of these innate immune receptors specifically in skeletal muscle metabolism. 2. Innate immune receptor expression in skeletal muscle Data on the expression of immune receptors in skeletal muscle is scarce, and as in every tissue, it is challenging to decipher whether the abundance of a specific mRNA or protein reflects the actual skeletal muscle fibre, or comes from the many other cells residing in the muscle: endothelial, fibroblasts, immune cells… Taking advantage of expression data from several gene arrays (Table 1), we established the baseline mRNA expression levels in human skeletal muscle biopsies, myofibres and primary muscle cells (Fig. 2). All innate immune receptors are detectable in skeletal muscle biopsies, but most of them fall below the median expression of the tissue. Only MYD88, NLRX1, NAIP, TLR4 and NLRC5 are expressed above the median. The expression levels of these receptors could also be dependent on the type of muscle: soleus having more TLR expressing cells than gastrocnemius muscle [8]. Interestingly, when comparing expression levels
Correspondence to: Karolinska Institutet, Department of Physiology and Pharmacology (FYFA), Integrative Physiology, von Eulers väg 4a, IV, SE-171 77 Stockholm, Sweden. E-mail address: [email protected] (N.J. Pillon).
http://dx.doi.org/10.1016/j.yexcr.2017.02.035 Received 30 December 2016; Accepted 20 February 2017 0014-4827/ © 2017 The Authors. Published by Elsevier Inc.
Please cite this article as: Pillon, N.J., Experimental Cell Research (2017), http://dx.doi.org/10.1016/j.yexcr.2017.02.035
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from muscle biopsies as well as isolated muscle fibres and primary myotubes. As a comparison, we extracted data on the mRNA levels of innate immune receptors in blood-derived human macrophages. As expected from professional pathogen-killing cells, macrophages possess large amounts of MYD88, TLR1/2/4 as well as several NLRs. Isolated muscle fibres show a very similar profile to the muscle biopsy with high expression of MYD88, TLR4 and TLR9 but surprisingly show high mRNA expression of NLRC5 and NLRC3. Primary skeletal muscle cells exhibit high expression of MYD88, TLR4 and TLR3 and significant amounts of NOD1 and NAIP. Overall, the relative expression of immune receptors is consistent between biopsies, isolated fibres and muscle cells. Expression levels change in amplitude between the different models, but the most abundant receptors are consistently MYD88, NRLX1, TLR4, NAIP, NOD1, NLRC5 and TLR9, which suggest that there are expressed by muscle cells themselves. However, even lowly expressed receptors may play important roles depending on the context and the presence or absence of their specific ligands or activators. Literature for metabolic studies involving all these receptors was searched in Pubmed, and the following sections summarise current knowledge regarding the immune receptors described in Fig. 2.
Fig. 1. Number of publications linking inflammation, diabetes and obesity. A PubMed query was performed with the R package “RSImed” using the keywords “(Diabetes OR Obesity) AND Inflammation” in association with metabolic tissues. Data is the number of papers published per 100.000 publications since 1995. The arrow is set in 2003, the year where two papers demonstrated an increased number of macrophages in adipose tissue from obese individuals [69,70].
between various tissues, skeletal muscle had the highest expression of TLR9 amongst all tissues and high expression of TLR4 and TLR5 [9]. Macrophages and other immune cells possess large amount of immune receptors, which could be contributing to the expression levels measured in tissues and biopsies. We therefore analysed gene arrays
3. Toll like receptors (TLR) TLRs are transmembrane proteins recognizing selective pathogen components. TLR3, TLR7, TLR9 are localized in the endosomal compartments whereas other TLRs sit at the plasma membrane [10].
Table 1 Datasets used for the analysis of innate immune receptors in skeletal muscle biopsies, cultured muscle cells and blood-derived macrophages. GEO
Sample
Array
Reference
GSE9103
Vastus Lateralis
[71]
GSE59363
Muscle biopsie
GSE43760
Vastus Lateralis
GSE41769
Vastus Lateralis
GSE17503
Paravertebral Muscle & Primary myotubes
GSE77212
Primary myotubes
GSE45819
Skeletal muscle stem cells
GSE44051
Primary myotubes
GSE26145
Primary myotubes
GSE27073
Primary myotubes
GSE50411
Primary myotubes
GSE28392
Single fibres isolated from Vastus Lateralis
GSE48280
MHC-I-positive myofibers
GSE30536
Blood-derived macrophage
GSE56591
Blood-derived macrophage
GSE10856
Blood-derived macrophage
GSE13670
Blood-derived macrophage
GSE16755
Blood-derived macrophage
GSE20484
Blood-derived macrophage
Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.1 ST Array Illumina humanRef-8 v2.0 expression beadchip Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Exon 1.0 ST Array Illumina humanRef-8 v2.0 expression beadchip Illumina HumanHT-12 V4.0 expression beadchip Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Gene 1.0 ST Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array Affymetrix Human Genome U133 Plus 2.0 Array
Whenever possible, arrays were re-analysed from raw data and normalized to allow relative comparison.
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[72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89]
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Fig. 2. Immune receptor expression in human skeletal muscle. Expression data from human muscle biopsies, isolated myofibres and primary myotubes as well as human blood-derived macrophages was extracted from publicly available gene arrays (Table 1). All biopsies, fibres and cells were from lean, healthy individuals. Only control and untreated conditions were kept to establish the baseline expression levels. Quantile normalization followed by median centring was performed to compare expression between different arrays.
tendency towards increased serum free fatty acids and reduced fasting glycemia [11]. Acute LPS injection (0.025 or 2 mg/kg, 6 h) lowers fasting blood glucose yet does not affect insulin tolerance [17]. But both chronic (100 μg/kg, daily for 4 wk) or acute (1 μg/kg, single dose) LPS injections reduce mitochondrial respiration. Mitochondria isolated from skeletal muscle from LPS-injected mice have reduced respiratory control ratio (RCR), and ADP- and FCCP-stimulated respiration [12,13] which does not fit with the decreased fatty acid oxidation observed in muscle cells in vitro. TLR4 expression is increased in skeletal muscle during high fat feeding or type 2 diabetes [18]. Mice lacking TLR4 have lower fasting glucose levels and reduced expression of lipogenic enzymes in muscle, which might account for their increased accumulation of triglycerides in skeletal muscle [19]. Deletion of TLR4 also confers significant protection in skeletal muscle against hyperlipidaemia-induced insulin resistance [20] as well as insulin resistance induced by hindlimb unloading [21]. In contrast, specific overexpression of TLR4 in skeletal muscle induces mild glucose intolerance and decreases fatty acid oxidation in lean mice [22]. When challenged with a high fat diet, TLR4-muscle-overexpressing mice gain more weight and display impaired insulin and glucose tolerance compared to their littermate controls [22]. This in vivo data suggests that TLR4 has deleterious effects on skeletal muscle metabolism. The canonical ligand for TLR4 is the bacterial factor LPS, but TLR4 has also been implicated in the activation of inflammatory signalling by saturated fatty acids. Studies using pharmacological agents like the TLR4 inhibitor TAK242, or silencing and knockdown strategies show that inhibition of TLR4 prevents some of the deleterious effects
All TLRs signal through MyD88 to the NF-κB transcription factor, although other alternative routes have been described [10]. 3.1. TLR4 The most studied Toll-like receptor in metabolism is TLR4 with more than 10,000 Pubmed hits for “TLR4 AND metabolism”. Its ligand is lipopolysaccharide (LPS), which has been used in both in vitro and in vivo studies to specifically activate the TLR4 pathway. In C2C12 and primary human skeletal muscle cells, acute stimulation with LPS (500 ng/mL, 2 h) modifies substrate preference, increasing glucose uptake and oxidation while decreasing fatty acid oxidation [11]. Acute exposure of C2C12 myotubes to LPS (100 ng/mL, 12 h) also increases mitochondrial respiration [12]. In both C2C12 and human primary myotubes, acute LPS exposure (50 ng/mL, 2 h) results in increased state 4 O respiration and reduced state 3 u respiration [13]. Paradoxically, chronic treatment with LPS (12–24 h) reduces mitochondrial respiration [13], and skeletal muscle cells exposed to LPS (100 ng/mL, 1–24 h) have impaired insulin signalling and insulinstimulated glucose uptake [14,15]. Overall, in vitro data in skeletal muscle cells suggest that TLR4 stimulation switches metabolism towards glycolysis while inhibiting fatty acid oxidation and inducing insulin resistance. This is strikingly similar to the response observed in immune cells, where inflammatory stimuli switches macrophage metabolism towards glycolysis and away from oxidative phosphorylation [16]. The situation in vivo appears more complex. Some in vitro effects are recapitulated in mice injected acutely with LPS, in which there is a 3
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3.4. TLR5
induced by palmitate or stearate. In L6 myotubes, inhibition of TLR4 activity reduces the capacity of palmitate or oleate to induce insulin resistance [15,20]. TLR4 deficiency ameliorates impaired insulin signalling in muscle and reduced insulin-mediated glucose metabolism induced by lipid infusion [23]. Similarly, in whole soleus muscles ex vivo, incubation with palmitate (1 mM, 6 h) impairs insulin-induced glucose uptake in WT mice, but not in TLR4-defective mice [24]. Some of this data may need to be revisited in light of the fact that Fetuin A has been proposed as a necessary co-factor for the activation of TLR4 by fatty acids [25]. Fetuin A is present in serum and experiments performed in the presence or absence of serum in the culture medium might therefore trigger different effects. In addition, possible traces of endotoxins contamination in fatty acid solutions might also conceal some of the true effects of fatty acids on cells in culture.
Mice deficient for TLR5 develop features of the metabolic syndrome with increased fat mass, altered blood lipid profile and insulin resistance, but the contribution of skeletal muscle per se remains to be investigated [38]. In vitro, skeletal muscle cells do not develop an inflammatory response to the TLR5 ligand flagellin alone [31], but no metabolic responses were measured in these cells. 3.5. TLR9 TLR9 is present in idiopathic inflammatory myopathies, mainly on cell infiltrates and on some injured myofibers [39]. TLR9-deficient non-obese diabetic mice have a significantly reduced incidence of diabetes, which seems to be due to a better beta-cell function [40]. Blockade of TLR9 delays autoimmune diabetes decreased IFN-α production and decreased diabetogenic CD8+ T cells [41]. Overall, TLR9 seems to be involved in the development of autoimmune diabetes. Although it is one of the most abundant TLR at the mRNA level in muscle, the putative role of TLR9 in skeletal muscle metabolism is currently unexplored.
3.2. MyD88 MyD88 is a universal adaptor molecule for Toll-like receptor signalling, involved in signal transduction from all TLRs [26]. Similarly to TLR4, high fat diet increases MyD88 in mouse skeletal muscle [27]. MYD88 mRNA is inversely correlated to quadriceps cross sectional area and muscle strength during recovery from hip fracture surgery [28], and studies have suggested MYD88 also plays a role in muscle growth and regeneration [29]. With regard to metabolism, insulin resistance can be induced in mice by 14 days of hindlimb uploading, which mainly, but not exclusively affects skeletal muscle. In this model, insulin resistance estimated with a glucose tolerance test and insulin signalling in muscle was prevented in MyD88-/- mice [30]. But studies are scarce and more work is needed to decipher the role of MyD88 specifically in skeletal muscle metabolism.
3.6. TLR3/7 TLR3 and TLR7 are almost absent in non-inflammatory muscle but significantly increased in inflammatory myopathies, although primarily detected in inflammatory cells infiltrating the tissue [42]. TLR3 is highly expressed in inclusion body myositis/polymyositis and HIVmyopathies, where muscle fibres express TLR3 in close proximity to infiltrating mononuclear cells [43]. TLR3 expression is reduced in primary myotubes cultured from obese insulin resistant subjects compared to cells cultured from obese insulin sensitive subjects [44]. In addition, TLR3-/- mice have normal whole body insulin sensitivity due to elevated insulin secretion, suggesting that TLR3 might plays a more important role in the pancreas comparatively to other tissues [45].
3.3. TLR2 The baseline expression of TLR2 is low in skeletal muscle (Fig. 2), and the NF-κB activation in skeletal muscle cells after TLR2 stimulation is 20-fold lower than the response to TLR4 agonists [31], suggesting that the role of TLR2 might be less important than TLR4. Nevertheless, TLR2 expression is increased in diet-induced obese mice [32], and skeletal muscle cells exposed to palmitate show enhanced TLR2 mRNA levels [33]. In contrast, no difference was observed in muscle biopsies from human volunteers with impaired glucose tolerance vs control subjects [34]. Insulin-induced IRS1 and Akt phosphorylation is reduced in skeletal muscle from high fat fed mice, and treatment with a TLR2 antisense oligonucleotide can partially reverse this insulin resistance [32]. Additionally, TLR2-/- mice are protected from the deleterious effects of a high fat diet as assessed by glucose tolerance and insulin sensitivity, but the metabolic benefits are likely independent from skeletal muscle. Indeed, skeletal muscle from TLR2-/- mice have increased Acox1 and Mcad mRNA, suggesting changes in beta-oxidation, but other genes involved in fatty acid uptake (Cd36, Pgc1a, Lcad) and inflammation (Cd68, F4/80, Mcp1) are unchanged. TLR2-/- mice have similar muscle triacylglycerols and glycogen content as their littermate controls [35] and in whole soleus muscles ex vivo, incubation with palmitate (1 mM, 6 h) impairs insulin-induced glucose uptake in WT mice, but this is not reversed in TLR2-/-muscles [24]. These contradictory data suggests that the regulation of metabolism by TLR2 might involve a cross-talk with other tissues and that skeletal muscle might not be the primary target of TLR2 in the metabolic syndrome. However, exercise-induced activation of MAPKs and c-Jun is reduced in muscle of TLR2-/- mice [36] and TLR2 knockdown diminishes immobilization-induced skeletal muscle inflammation and atrophy [37], suggesting that TLR2 might be involved in the skeletal muscle response to contraction and atrophy.
3.7. Other TLRs Increased TLR1 and decreased TLR6 mRNA has been reported in response to a high fat diet in skeletal muscle from female mice [35], but to date the role of TLR1, TLR8, TLR6 and TLR10 on skeletal muscle metabolism remain to be investigated. 4. NOD-like receptors (NLR) The NLR family includes several members classified in subfamilies according either to their N-terminal effector domain or their phylogenetic relationships [46,47]. They are all intracellular sensors recognizing either pathogen or danger associated molecular patterns (PAMPs and DAMPs), and some of them are involved in the formation of inflammasomes. 4.1. NOD1/2 NOD1/2 are receptors for intracellular pathogens, recognizing bacterial molecules containing D-glutamyl-meso-diaminopimelic acid and peptidoglycans respectively. Activation of NOD2 by muramyl dipeptide (MDP) in L6 skeletal muscle induces inflammation with activation of the NF-κB pathways and stress kinases. This is associated with insulin resistance as MDP reduces insulin-stimulated signalling and glucose uptake [48]. On the contrary, NOD1 ligands, such as iEDAP, FK156, and FK565, have no significant effect on glucose uptake and insulin resistance in L6 skeletal muscle cells [48]. MDP increases ROS production and carbonyls and reduces mitochondrial membrane potential, suggesting that NOD2-mediated insulin resistance could be 4
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therefore surprising to find it so highly expressed in skeletal muscle biopsies and cells. NLRX1 expression is decreased in the liver of mice fed a high fat diet and even further decreased in obese mice when treated with LPS [60]. NLRX1 seems to negatively regulate TLR-NF-κB signalling and therefore have anti-inflammatory effects [61,62], but whether it plays any role in metabolism is yet to be explored.
due to oxidative stress [49]. In vivo, activation of NOD1 induces insulin resistance. NOD1 ligand-challenged mice show a marked reduction in insulin-dependent phosphorylation of AS160 in skeletal muscle [17]. On the contrary, NOD2 ligands only modestly reduced peripheral glucose disposal. NOD2 activation by MDP failed to alter fasting blood glucose or insulin tolerance when assessed by ITT but reduced peripheral glucose utilization measured with a euglycemic hyperinsulinemic clamp. NOD1/2 double knockout mice are protected from high fat dietinduced inflammation, lipid accumulation, and peripheral insulin intolerance [17]. Data from in vivo experiments suggest that NOD1 activation likely targets liver and adipose tissue more directly than skeletal muscle metabolism, while data from in vitro experiments suggest that insulininduced glucose uptake in skeletal muscle cells is more sensitive to NOD2 ligands. More studies are necessary to better characterize this differential effect of NOD1/2 ligands on muscle metabolism.
4.6. NLRPs Skeletal muscle expression of NRLP3 in humans is higher in skeletal muscle biopsies from subjects eating a high-palmitate diet compared to a low-palmitate/high-oleate diet [63]. Two studies pointed out the role of the NLRP3 inflammasome in sensing saturated fatty acids and regulating cell metabolism [64,65]. In Nlrp3−/− mice, insulin-induced phosphorylation of Akt in skeletal muscle tissues is similar or potentiated compared to the littermate controls [64,65]. In vitro, perilipin 2 overexpression in C2C12 cells leads to accumulation of triglycerides and an increased expression of NLRP3 along with an impaired insulin-induced glucose uptake. Silencing of NLRP3 partially reverses perilipin-induced insulin resistance in skeletal muscle cells [66]. NLRP3 inflammasome seems to be also involved in myopathies, as NLRP3 is up-regulated and activated in dysferlin-deficient muscle [67]. Apart from NLRP3 very little is known about the role of the other NLRP molecules in skeletal muscle metabolism.
4.2. CIITA CIITA (Class II Major Histocompatibility Complex Transactivator) is a transcriptional coactivator abundant in human leukocytes. High-fat diet increases CITTA mRNA in adipose tissue, and regulates tissue inflammation [50]. Whole body knockout of CIITA protects non-obesediabetic mice from type-1 diabetes despite infiltration of immune cells in the pancreas [51], but the involvement of CITTA in type 2 diabetes in unexplored. In C2C12 mouse skeletal muscle cells, IFNγ disrupts the expression of genes involved in metabolism and energy expenditure by repressing the expression and activity of SIRT1. These deleterious effects of INFγ are mediated through an induction of CIITA which is recruited to the SIRT1 promoter and promotes down-regulation of SIRT1 transcription [52]. CIITA also represses Pdk4 transcription by directly targeting SIRT1 in a mechanism that involved HDAC4 [53,54]. CIITA is also involved in IFNγ-induced inhibition of myogenesis by binding to and inhibiting myogenin activity [55], suggesting that it can potentially affect many functions in skeletal muscle cells. Yet, data on the possible role of CITTA in regulating expression of metabolic genes is solely based on results from C2C12 cultured cells and need to be confirmed in other models as well as in vivo.
5. Conclusion In comparison to adipose tissue and liver, the study of innate immune receptors in skeletal muscle has been neglected, and the role and possible influence on whole body metabolism of these receptors remains largely unknown. In addition to the expression of the receptors on myocytes, innate immune receptors expressed on resident immune cells could also affect the whole tissue by regulating metabolism through cell-cell communication [4]. For instance, in vitro experiments provide proof of concept that macrophages exposed to fatty acids release cytokines that impact muscle insulin sensitivity [68] and on the other hand that muscle cells have the ability to secrete factors affecting the immune system [5,7]. In the context of a worldwide epidemic of obesity and diabetes and a lack of efficient therapeutic strategies to treat or prevent it, targeting skeletal muscle immunometabolic processes could potentially provide novel strategies to improve insulin sensitivity.
4.3. NAIP NAIP deletions are associated with an early onset and worse outcome in spinal muscular atrophy [56], but no other role in skeletal muscle has been described.
Acknowledgments This work was supported by the Novo Nordisk Foundation Initiative on Immunometabolism (NNF15CC0018346), the Swedish Research Council (2012-1760), the Swedish Diabetes Association (DIA2015-032), the Stockholm County Council (20150326), Diabetes Wellness Network Sweden (783_2015PG) and the Strategic Research Programme in Diabetes at Karolinska Institutet (Swedish Research Council grant No 2009-1068). NJP was supported by a Marie Skłodowska-Curie Fellowship (H2020-MSCA-IF-2015, 704978) and grants from the Lars Hiertas Minne Foundation (FO2015-0507, FO2016-0283).
4.4. NLRCs Infection with Salmonella induces muscle wasting, which can be prevented by colonization of the mice by a specific strain of Escherichia coli (O21:H+). In the presence of this specific E. coli strain, signalling through insulin-like growth factor 1/phosphatidylinositol 3-kinase/ AKT was preserved in skeletal muscle. This effect was mediated through NLRC4 and the production of IGF1 by the adipose tissue, but the study did not address whether NLRC4 in the skeletal muscle was involved [57]. To date, the role of the NLRC receptors in skeletal muscle is unexplored.
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