Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy

Huang, Nancy Ν.; Kny, Melanie; Riediger, Fabian; Büsch, Katharina; Schmidt, Sibylle; Luft, Friedrich C.; Slevogt, Hortense; Fielitz, Jens

doi:10.1186/s40635-016-0115-0

Cited by 67 publications

(115 citation statements)

References 53 publications

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“…Recently, we reported that SAA1 increases Il6 expression in murine and human myocytes in vitro . In addition, IL6 expression is increased in muscle of ICUAW patients and septic mice . We found that muscular TLR2 and TLR4 expression is increased during sepsis in patients and mice, that SAA1 increases Tlr2 and Tlr4 expression in myotubes, and that SAA1 via TLR2 and TLR4 increases Il6 expression in myocytes.…”

Section: Discussionmentioning

confidence: 64%

“…Recently, others and we showed that primarily fast‐twitch fibers undergo atrophy in ICUAW patients and septic mice . Therefore, we tested if BMS‐345541 protects fast/type‐II myofibers from atrophy in sepsis.…”

Section: Resultsmentioning

confidence: 99%

“…We found that SAA1‐treatment caused myotube atrophy ( Figure A) as indicated by a leftward‐shift of the frequency‐distribution histogram ( Figure B) and a decrease in the mean myotube diameter ( Figure E). Recently, we reported that inflammation causes a decrease in myosin heavy chain (MyHC) proteins in muscle and that the ubiquitin proteasome system, especially the muscle specific E3‐ligase MuRF1, was involved . We therefore next investigated whether SAA1‐induced atrophy coincided with a decrease in MyHC and an increase in MuRF1 protein content.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we reported that inflammation causes a decrease in myosin heavy chain (MyHC) proteins in muscle and that the ubiquitin proteasome system, especially the muscle specific E3-ligase MuRF1, was involved. 12,34 We therefore next investigated whether SAA1-induced atrophy coincided with a decrease in MyHC and an increase in MuRF1 protein content. Western blot analysis showed that SAA1-treatment led to a decrease in Myh7 and an increase in MuRF1 protein contents in C2C12 myotubes ( Figure 2F).…”

Section: Serum Amyloid A1 Toll-like Receptors and Nf-κbmentioning

confidence: 99%

“…Inflammation and sepsis clearly increase the risk for ICUAW, and inflammatory cytokines are associated with the incidence of ICUAW . Skeletal muscle and skeletal myocytes are targeted by inflammatory cytokines, such as interleukin 1β (IL1β) and IL6, causing myocyte atrophy . Our attention was drawn to serum amyloid A1 (SAA1) that is associated with inflammation and acute‐phase responses during sepsis …”

Section: Introductionmentioning

confidence: 99%

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Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

Hahn

Kny

Pablo‐Tortola

et al. 2019

J cachexia sarcopenia muscle

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Background Critically ill patients frequently develop muscle atrophy and weakness in the intensive‐care‐unit setting [intensive care unit‐acquired weakness (ICUAW)]. Sepsis, systemic inflammation, and acute‐phase response are major risk factors. We reported earlier that the acute‐phase protein serum amyloid A1 (SAA1) is increased and accumulates in muscle of ICUAW patients, but its relevance was unknown. Our objectives were to identify SAA1 receptors and their downstream signalling pathways in myocytes and skeletal muscle and to investigate the role of SAA1 in inflammation‐induced muscle atrophy. Methods We performed cell‐based in vitro and animal in vivo experiments. The atrophic effect of SAA1 on differentiated C2C12 myotubes was investigated by analysing gene expression, protein content, and the atrophy phenotype. We used the cecal ligation and puncture model to induce polymicrobial sepsis in wild type mice, which were treated with the IкB kinase inhibitor Bristol‐Myers Squibb (BMS)‐345541 or vehicle. Morphological and molecular analyses were used to investigate the phenotype of inflammation‐induced muscle atrophy and the effects of BMS‐345541 treatment. Results The SAA1 receptors Tlr2, Tlr4, Cd36, P2rx7, Vimp, and Scarb1 were all expressed in myocytes and skeletal muscle. Treatment of differentiated C2C12 myotubes with recombinant SAA1 caused myotube atrophy and increased interleukin 6 (Il6) gene expression. These effects were mediated by Toll‐like receptors (TLR) 2 and 4. SAA1 increased the phosphorylation and activity of the transcription factor nuclear factor ‘kappa‐light‐chain‐enhancer' of activated B‐cells (NF‐κB) p65 via TLR2 and TLR4 leading to an increased binding of NF‐κB to NF‐κB response elements in the promoter region of its target genes resulting in an increased expression of NF‐κB target genes. In polymicrobial sepsis, skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with the atrophy response. Inhibition of NF‐κB signalling by BMS‐345541 increased survival (28.6% vs. 91.7%, P < 0.01). BMS‐345541 diminished inflammation‐induced atrophy as shown by a reduced weight loss of the gastrocnemius/plantaris (vehicle: −21.2% and BMS‐345541: −10.4%; P < 0.05), tibialis anterior (vehicle: −22.7% and BMS‐345541: −17.1%; P < 0.05) and soleus (vehicle: −21.1% and BMS‐345541: −11.3%; P < 0.05) in septic mice. Analysis of the fiber type specific myocyte cross‐sectional area showed that BMS‐345541 reduced inflammation‐induced atrophy of slow/type I and fast/type II myofibers compared with vehicle‐treated septic mice. BMS‐345541 reversed the inflammation‐induced atrophy program as indicated by a reduced expression of the atrogenes Trim63/MuRF1, Fbxo32/Atrogin1, and Fbxo30/MuSA1. Conclusions SAA1 activates the TLR2/TLR4//NF‐κB p65 signalling pathway to cause myocyte atrophy. Systemic inhibition of the NF‐κB pathway reduced muscle atrophy and increased survival of septic mice. The SAA1/TLR2/TLR4//NF‐κB p65 atrophy pathway could have utility in combatting ICUAW.

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Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Serum Amyloid A1 Toll-like Receptors and Nf-κbmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

Hahn

Kny

Pablo‐Tortola

et al. 2019

J cachexia sarcopenia muscle

Self Cite

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Immunological Behavior Analysis of Muscle Cells under IFN‐γ Stimulation in Vitro and in Vivo

Ding

Huang

Zhu

et al. 2018

The Anatomical Record

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Muscle cells could serve as antigen-presenting cells, and participate in the activation of immune response. Immunological characteristics of muscle cells, and their capacities to equip themselves with immunorelevant molecules, remain to be elucidated. In this study, we investigated the immunological properties of myoblasts and differentiated myotubes in vitro and in vivo, under the IFN-γ induced inflammatory condition. We found that the fused C C myotubes are more sensitive to inflammatory stimulation, and significantly upregulated the expression levels of MHC-I/II and TLR3/7 molecules, than that of proliferated myoblasts. As well, some co-stimulatory/-inhibitory molecules, including CD40, CD86, ICAM-I, ICOS-L, and PD-L1, were prominently upregulated in IFN-γ induced myotubes. Notably, we detected the protein levels of ASC, NLRP3, and Caspase-1 increased in stimulated myotubes, and IL-1β in cell culture supernatant, implying the activation of NLRP3 inflammasomes in IFN-γ treated myotubes. The pro-inflammatory cytokines and chemokines mRNA levels in IFN-γ induced C C myotubes and myoblasts, involving IL-1, IL-6, and MCP-1, increased markedly. T cell activation test further verified IFN-γ induced C C myotubes prompt to the proliferation of the splenic CD4 and CD8 T cells. In Cardiotoxin-damaged tibialis anterior (TA) muscle, some regenerated myofibers expressed both MHC class I and class II molecules under IFN-γ enhanced inflammatory condition. Thus, our work demonstrates that muscle cells are active participants of local immune reactions. Anat Rec, 301:1551-1563, 2018. © 2018 Wiley Periodicals, Inc.

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Targeting interleukin‐1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis

Cheung

Sheng

Zheng

et al. 2021

J cachexia sarcopenia muscle

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Background Ctns À/À mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Inflammatory cytokines such as interleukin (IL)-1 trigger inflammatory cascades and may be an important cause for cachexia. We employed genetic and pharmacological approaches to investigate the effects of IL-1 blockade in Ctns À/À mice. Methods We generated Ctns À/À Il1β À/À mice, and we treated Ctns À/À and wild-type control mice with IL-1 receptor antagonist, anakinra (2.5 mg/kg/day, IP) or saline as vehicle for 6 weeks. In each of these mouse lines, we characterized the cachexia phenotype consisting of anorexia, loss of weight, fat mass and lean mass, elevation of metabolic rate, and reduced in vivo muscle function (rotarod activity and grip strength). We quantitated energy homeostasis by measuring the protein content of uncoupling proteins (UCPs) and adenosine triphosphate in adipose tissue and skeletal muscle. We measured skeletal muscle fiber area and intramuscular fatty infiltration. We also studied expression of molecules regulating adipose tissue browning and muscle mass metabolism. Finally, we evaluated the impact of anakinra on the muscle transcriptome in Ctns À/À mice. Results Skeletal muscle expression of IL-1β was significantly elevated in Ctns À/À mice relative to wild-type control mice. Cachexia was completely normalized in Ctns À/À Il1β À/À mice relative to Ctns À/À mice. We showed that anakinra attenuated the cachexia phenotype in Ctns À/À mice. Anakinra normalized UCPs and adenosine triphosphate content of adipose tissue and muscle in Ctns À/À mice. Anakinra attenuated aberrant expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2/Pgf2α, Tlr2, Myd88, and Traf6) in inguinal white adipose tissue in Ctns À/À mice. Moreover, anakinra normalized gastrocnemius weight and fiber size and attenuated muscle fat infiltration in Ctns À/À mice. This was accompanied by correction of the increased muscle wasting signalling pathways (increased protein content of ERK1/2, JNK, p38 MAPK, and nuclear factor-κB p65 and mRNA expression of Atrogin-1 and Myostatin) and the decreased myogenesis process (decreased mRNA expression of MyoD and Myogenin) in the gastrocnemius muscle of Ctns À/À mice. Previously, we identified the top 20 differentially expressed skeletal muscle genes in Ctns À/À mice by RNAseq. Aberrant expression of these 20 genes have been implicated in muscle wasting, increased energy expenditure, and lipolysis. We showed that anakinra attenuated 12 of those top 20 differentially expressed muscle genes in Ctns À/À mice. Conclusions Anakinra may provide a targeted novel therapy for patients with infantile nephropathic cystinosis.

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Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy

Cited by 67 publications

References 53 publications

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

Immunological Behavior Analysis of Muscle Cells under IFN‐γ Stimulation in Vitro and in Vivo

Targeting interleukin‐1 for reversing fat browning and muscle wasting in infantile nephropathic cystinosis

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