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Cited by 225Muscle Physiology and DisordersCytokine Signaling Pathways and InteractionsSepsis Diagnosis and Treatment

Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting

Open access
Zanders, Lukas, Kny, Melanie, Hahn, Alexander, Schmidt, Sibylle, Wundersitz, Sebastian, Todiras, Mihail, Lahmann, Ines, Bandyopadhyay, Arnab +6 more·2022·Journal of Cachexia, Sarcopenia and Muscle
DOI 10.1002/jcsm.12867PMC PMC8818599
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Abstract

Background: Sepsis and inflammation can cause intensive care unit‐acquired weakness (ICUAW). Increased interleukin‐6 (IL‐6) plasma levels are a risk factor for ICUAW. IL‐6 signalling involves the glycoprotein 130 (gp130) receptor and the JAK/STAT‐pathway, but its role in sepsis‐induced muscle wasting is uncertain. In a clinical observational study, we found that the IL‐6 target gene, SOCS3 , was increased in skeletal muscle of ICUAW patients indicative for JAK/STAT‐pathway activation. We tested the hypothesis that the IL‐6/gp130‐pathway mediates ICUAW muscle atrophy. Methods: We sequenced RNA (RNAseq) from tibialis anterior (TA) muscle of cecal ligation and puncture‐operated (CLP) and sham‐operated wildtype (WT) mice. The effects of the IL‐6/gp130/JAK2/STAT3‐pathway were investigated by analysing the atrophy phenotype, gene expression, and protein contents of C2C12 myotubes. Mice lacking Il6st , encoding gp130, in myocytes (cKO) and WT controls, as well as mice treated with the JAK2 inhibitor AG490 or vehicle were exposed to CLP or sham surgery for 24 or 96 h. Results: Analyses of differentially expressed genes in RNAseq (≥2‐log2‐fold change, P < 0.01) revealed an activation of IL‐6‐signalling and JAK/STAT‐signalling pathways in muscle of septic mice, which occurred after 24 h and lasted at least for 96 h during sepsis. IL‐6 treatment of C2C12 myotubes induced STAT3 phosphorylation (three‐fold, P < 0.01) and Socs3 mRNA expression (3.1‐fold, P < 0.01) and caused myotube atrophy. Knockdown of Il6st diminished IL‐6‐induced STAT3 phosphorylation (−30.0%; P < 0.01), Socs3 mRNA expression, and myotube atrophy. JAK2 (− 29.0%; P < 0.01) or STAT3 inhibition (−38.7%; P < 0.05) decreased IL‐6‐induced Socs3 mRNA expression. Treatment with either inhibitor attenuated myotube atrophy in response to IL‐6. CLP‐operated septic mice showed an increased STAT3 phosphorylation and Socs3 mRNA expression in TA muscle, which was reduced in septic Il6st ‐cKO mice by 67.8% ( P < 0.05) and 85.6% ( P < 0.001), respectively. CLP caused a loss of TA muscle weight, which was attenuated in Il6st ‐cKO mice (WT: −22.3%, P < 0.001, cKO: −13.5%, P < 0.001; WT vs. cKO P < 0.001). While loss of Il6st resulted in a reduction of MuRF1 protein contents, Atrogin‐1 remained unchanged between septic WT and cKO mice. mRNA expression of Trim63 /MuRF1 and Fbxo32 /Atrogin‐1 were unaltered between CLP‐treated WT and cKO mice. AG490 treatment reduced STAT3 phosphorylation (−22.2%, P < 0.05) and attenuated TA muscle atrophy in septic mice (29.6% relative reduction of muscle weight loss, P < 0.05). The reduction in muscle atrophy was accompanied by a reduction in Fbxo32 /Atrogin‐1‐mRNA (−81.3%, P < 0.05) and Trim63 /MuRF1‐mRNA expression (−77.6%, P < 0.05) and protein content. Conclusions: IL‐6 via the gp130/JAK2/STAT3‐pathway mediates sepsis‐induced muscle atrophy possibly contributing to ICUAW.

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Written from the paper’s full text.

TL;DR

Sepsis activates IL-6/gp130/JAK2/STAT3 signaling in skeletal muscle, and this pathway mediates sepsis-induced muscle atrophy in mice and myotubes. Genetic or pharmacological inhibition of gp130/JAK2/STAT3 attenuates muscle wasting, suggesting a possible target for ICU-acquired weakness.

Key findings

  • In muscle biopsies from critically ill patients, SOCS3 mRNA was increased in vastus lateralis at Day 5 and Day 15 after ICU admission versus controls, indicating IL-6/JAK/STAT pathway activation.
  • RNAseq of tibialis anterior from cecal ligation and puncture (CLP) mice showed activation of IL-6 and JAK/STAT signaling after 24 h and 96 h; Il6, Il6st, and Il6ra expression increased.
  • IL-6 treatment of C2C12 myotubes induced STAT3 phosphorylation (three-fold, P < 0.01), Socs3 mRNA (3.1-fold, P < 0.01), and myotube atrophy; Il6st knockdown reduced IL-6-induced STAT3 phosphorylation (−30.0%; P < 0.01), Socs3 expression, and atrophy. JAK2 inhibition (−29.0%; P < 0.01) or STAT3 inhibition (−38.7%; P < 0.05) decreased IL-6-induced Socs3 expression.
  • In septic mice, myocyte-specific Il6st deletion reduced STAT3 phosphorylation and Socs3 expression by 67.8% (P < 0.05) and 85.6% (P < 0.001), respectively, and attenuated TA weight loss (WT: −22.3%, cKO: −13.5%; P < 0.001). AG490 reduced STAT3 phosphorylation (−22.2%, P < 0.05) and attenuated TA muscle atrophy (29.6% relative reduction of muscle weight loss, P < 0.05), with reduced Fbxo32/Atrogin-1 and Trim63/MuRF1 mRNA and protein.

Methods

  • Clinical observational analysis of SOCS3 mRNA in vastus lateralis biopsies from critically ill, mechanically ventilated patients at high risk for ICUAW (SOFA score ≥8 on three consecutive days within the first 5 days after ICU admission) at Day 5 and Day 15, with age- and gender-matched elective orthopaedic surgery controls.
  • Male Il6st conditional knockout mice (Il6st loxP/loxP; Pax7-Cre) and WT littermates underwent CLP or sham surgery for 24 or 96 h; separate male C57BL/6J mice received JAK2 inhibitor AG490 or vehicle before CLP/sham and every 24 h for 96 h. Analyses included RNAseq of TA muscle, qRT-PCR, Western blot, histology with metachromatic ATPase staining for myocyte cross-sectional area, and plasma IL-6 ELISA.
  • C2C12 myotubes were differentiated for 5 days and treated with recombinant IL-6, Il6st siRNA, JAK2 inhibitor AG490, STAT3 inhibitors C188-9 or S3i-201, and/or insulin; outcomes included STAT3 phosphorylation, Socs3 expression, myotube diameter, and IRS-1/Akt phosphorylation. Statistics used paired t tests, Mann–Whitney U tests, and significance at P ≤ 0.05.

Limitations

  • Stated: in vitro experiments used murine C2C12 myotubes; further analyses of primary murine and/or human myocytes are needed to independently confirm the findings.
  • Stated: mice were 12–20 weeks old, corresponding to a young age in humans; further studies in mature (12-month-old) and aged (24-month-old) mice are needed, and only male mice were used, so sex-specific studies are needed.
  • Evident from the text: human evidence is observational biopsy expression data, so causality of IL-6/gp130/JAK2/STAT3 signaling in human ICUAW is not established by this study.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/jcsm.12867

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

25 of 38 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    SOCS3 acts as a negative feedback inhibitor of cytokine signalling by inhibition of JAK1, JAK2, and Tyk2.

    “SOCS3 acts as a negative feedback inhibitor of cytokine signalling by inhibition of JAK1, JAK2, and Tyk2.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Babon JJ, Kershaw NJ, Murphy JM, Varghese LN, Laktyushin A, Young SN, et al. Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity 2012; 36: 239– 250. 22342841 PMC3299805 source
  • Premisecitation

    IL-6 regulates protein homeostasis in skeletal muscle.

    “IL‐6 regulates protein homeostasis in the skeletal muscle.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [13] Tierney MT, Aydogdu T, Sala D, Malecova B, Gatto S, Puri PL, et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat Med 2014; 20: 1182– 1186. 25194572 PMC4332844 source

      The Abstract says sustained systemic IL-6 elevation contributes to muscle atrophy, while IL-6 also regulates satellite cell–mediated hypertrophy. That supports a role in skeletal muscle maintenance, but the paper does not establish regulation of protein homeostasis specifically, such as protein synthesis or degradation. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [14] Hoene M, Runge H, Haring HU, Schleicher ED, Weigert C. Interleukin‐6 promotes myogenic differentiation of mouse skeletal muscle cells: role of the STAT3 pathway. Am J Physiol Cell Physiol 2013; 304: C128– C136. 23114963 source
  • Premisecitation

    Increased IL-6 plasma level is a risk factor for Critical Illness Myopathy (CIM) in patients.

    “Based on these data and together with our observation that increased IL‐6 plasma level is a risk factor for Critical Illness Myopathy (CIM) in patients, 8 we hypothesized”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Weber‐Carstens S, Deja M, Koch S, Spranger J, Bubser F, Wernecke KD, et al. Risk factors in critical illness myopathy during the early course of critical illness: a prospective observational study. Crit Care 2010; 14: R119. 20565863 PMC2911767 source
  • Premisecitation

    AG490 leads to a reduction in TNF plasma levels in septic mice.

    “Peña et al. showed that AG490 leads to a reduction in TNF plasma levels in septic mice. 29”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Peña G, Cai B, Deitch EA, Ulloa L. JAK2 inhibition prevents innate immune responses and rescues animals from sepsis. J Mol Med (Berl) 2010; 88: 851– 859. 20393690 PMC3083634 source
  • Findingown data

    In septic Il6st-cKO mice, STAT3 phosphorylation in TA muscle is reduced by 67.8% (P<0.05) compared to septic WT mice.

    “which was reduced in septic Il6st‐cKO mice by 67.8% (P < 0.05) and 85.6% (P < 0.001), respectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 36

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Acute increase in systemic IL-6 promotes muscle growth and hypertrophy, while sustained elevation, as in cancer or diabetes, causes muscle atrophy.

    “While an acute increase in systemic IL‐6 promotes muscle growth and hypertrophy, its sustained elevation, as occurring in cancer or diabetes, causes muscle atrophy.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge DC, Khuri S, Koniaris LG, et al. STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLoS One 2011; 6: e22538, 10.1371/journal.pone.0022538 21799891 PMC3140523 source

      The Discussion (page unavailable) says that elevated circulating IL-6 accompanies muscle wasting in the C26 cancer model and that administering IL-6 to mice can induce systemic muscle wasting. It does not say that an acute systemic IL-6 increase promotes muscle growth or hypertrophy, or establish the claimed effect in diabetes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [16] Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R, Puzis L, et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL‐6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab 2012; 303: E410– E421. 22669242 PMC3423125 source

      The Results (page not provided) show that sustained IL-6 exposure caused progressive muscle wasting in mice, supporting the cancer-related atrophy claim. The paper does not establish that an acute systemic IL-6 increase promotes muscle growth or hypertrophy, and the cited passages do not address diabetes as a setting for IL-6-driven atrophy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    MuRF1 and Atrogin-1 are key factors for ubiquitin-proteasome system-mediated protein degradation in muscle atrophy.

    “The E3 ligase muscle RING‐finger protein‐1 (MuRF1), encoded by Trim63, and the F‐Box protein Atrogin‐1, encoded by Fbxo32, are key factors for ubiquitin‐proteasome system‐mediated protein degradation in muscle atrophy.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 2001; 294: 1704– 1708. 11679633 source

      The main text (page unavailable) calls MuRF1 and MAFbx critical regulators of muscle atrophy and describes their role as ubiquitin ligases that target proteins for proteasomal degradation. It qualifies their regulation of muscle-protein degradation as “most likely,” rather than establishing that mechanism definitively. The copy uses MAFbx and does not verify the Atrogin-1, Trim63, or Fbxo32 names in the citing sentence. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    IL-1β and SAA1 signalling converge on NF-κB and increase expression of IL-6.

    “Both IL‐1β and SAA1 signalling converge on the transcription factor NF‐ĸB (nuclear factor ‘kappa‐light‐chain‐enhancer’ of activated B‐cells) and increase the expression of interleukin 6 (IL‐6).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [10] Huang N, Kny M, Riediger F, Busch K, Schmidt S, Luft FC, et al. Deletion of Nlrp3 protects from inflammation‐induced skeletal muscle atrophy. Intensive Care Med Exp 2017; 5: 3. 28097512 PMC5241267 source

      The Results section ('IL-1β induces myocyte atrophy in vitro'; page unavailable) reports that IL-1β activates NF-κB-dependent signaling and increases Il6 expression in myocytes. The Discussion describes SAA1 as part of a possible inflammatory feedback loop, but does not say that SAA1 activates NF-κB or increases IL-6 expression. The claimed convergence of both signals on NF-κB is therefore not established by this paper. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [11] Langhans C, Weber‐Carstens S, Schmidt F, Hamati J, Kny M, Zhu X, et al. Inflammation‐induced acute phase response in skeletal muscle and critical illness myopathy. PLoS One. 2014; 9: e92048, 10.1371/journal.pone.0092048 24651840 PMC3961297 source

      The Results section on SAA1 production in CIM patients reports that IL-6 increases SAA1 expression in myotubes, not that SAA1 increases IL-6 expression. The Discussion mentions IL-1β in relation to hepatic SAA synthesis and NF-κB in relation to GLUT4 regulation, but does not connect IL-1β and SAA1 signalling through NF-κB to increased IL-6 expression (page numbers unavailable). (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [12] Hahn A, Kny M, Pablo‐Tortola C, Todiras M, Willenbrock M, Schmidt S, et al. Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors. J Cachexia Sarcopenia Muscle 2020; 11: 103– 119. 31441598 PMC7015249 source

      The Results (‘Serum amyloid A1, Toll-like receptors, and NF-κB’; page unavailable) show that SAA1 activates NF-κB and increases Il6 expression in myotubes. The paper does not establish the other half of the claimed convergence: that IL-1β signalling activates NF-κB and increases IL-6. Its Introduction instead mentions SAA1 promoting IL-1β activation and release in macrophages. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Inflammation and sepsis are major risk factors for ICUAW.

    “Inflammation and sepsis are major risk factors for ICUAW.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [8] Weber‐Carstens S, Deja M, Koch S, Spranger J, Bubser F, Wernecke KD, et al. Risk factors in critical illness myopathy during the early course of critical illness: a prospective observational study. Crit Care 2010; 14: R119. 20565863 PMC2911767 source

      The Discussion says systemic inflammation and sepsis-related organ dysfunction are major triggers for critical illness myopathy (CIM), and the Conclusions identify systemic inflammation as the main risk factor during early critical illness. The Introduction connects CIM to ICU-acquired muscle weakness, but the study assesses CIM rather than ICU-acquired weakness as a whole; it also specifies sepsis-related organ dysfunction, not sepsis alone. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [9] Winkelman C. The role of inflammation in ICU‐acquired weakness. Crit Care 2010; 14: 186. 20727229 PMC2945106 source

      The Abstract says systemic inflammatory pathology is suggested to be the most significant risk factor for ICU-acquired weakness, but calls that finding equivocal. It also notes differences in septic shock between patient groups; it does not establish sepsis itself as a major risk factor. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    IL-1β and SAA1 promote muscle atrophy in sepsis, and their inhibition attenuates sepsis-induced muscle atrophy in mice.

    “Previously, we reported that interleukin 1β (IL‐1β) 10 and the acute‐phase protein serum amyloid A1 (SAA1) 11 , 12 promote muscle atrophy in sepsis, and that their inhibition attenuated sepsis‐induced muscle atrophy in mice.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [10] Huang N, Kny M, Riediger F, Busch K, Schmidt S, Luft FC, et al. Deletion of Nlrp3 protects from inflammation‐induced skeletal muscle atrophy. Intensive Care Med Exp 2017; 5: 3. 28097512 PMC5241267 source
    • cites [11] Langhans C, Weber‐Carstens S, Schmidt F, Hamati J, Kny M, Zhu X, et al. Inflammation‐induced acute phase response in skeletal muscle and critical illness myopathy. PLoS One. 2014; 9: e92048, 10.1371/journal.pone.0092048 24651840 PMC3961297 source

      The Results section on SAA1 expression across species (page unavailable) reports increased muscular SAA1 in septic mice, and the Discussion implicates SAA1 in inflammation-induced muscle atrophy. The paper does not report that inhibiting SAA1 attenuated sepsis-induced muscle atrophy in mice. The IL-1β assertion has a separate citation in the citing sentence and is not assessed against this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [12] Hahn A, Kny M, Pablo‐Tortola C, Todiras M, Willenbrock M, Schmidt S, et al. Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors. J Cachexia Sarcopenia Muscle 2020; 11: 103– 119. 31441598 PMC7015249 source

      The Introduction says SAA1 causes myocyte atrophy through the TLR2/TLR4/NF-κB pathway, and the Results report that inhibiting NF-κB with BMS-345541 attenuated muscle atrophy in septic mice. The mouse experiment inhibited a downstream pathway, not SAA1 itself; this paper therefore does not establish that inhibiting SAA1 attenuated atrophy in mice. The sentence attaches a separate citation to IL-1β. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    IL-6 signalling through gp130 activates JAK and STAT, leading to expression of target genes such as SOCS3.

    “In both pathways, the activated IL‐6R‐gp130 complex binds and activates the Janus kinase (JAK) family of tyrosine kinases, primarily JAK1, JAK2, and TYK2, which phosphorylate the cytoplasmatic tail of gp130, enabling the association of the Signal Transducer and Activator of Transcription (STAT), mainly STAT1 and STAT3.”
    • Also stated in: § Introduction · plain
      “Phosphorylated STAT (i.e. STAT3 Y705) proteins dimerize and translocate to the nucleus where they control the expression of their target genes, such as Suppressor of Cytokine Signalling 3 (SOCS3).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [17] Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995; 82: 241– 250. 7543024 source
    • cites [18] Heinrich PC, Behrmann I, Muller‐Newen G, Schaper F, Graeve L. Interleukin‐6‐type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334: 297– 314. 9716487 PMC1219691 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    gp130 is shared by the IL-6 cytokine family consisting of IL-6, IL-11, CNF, LIF, OSM, CT-1, CLCF1, and IL-27.

    “As a beta‐receptor, gp130 is shared by the IL‐6 cytokine family consisting of IL‐6, IL‐11, CNF, LIF, OSM, CT‐1, CLCF1, and IL‐27. 37”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Tanaka T, Narazaki M, Kishimoto T. IL‐6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6: a016295, 10.1101/cshperspect.a016295 25190079 PMC4176007 source

      The IL-6 receptor-mediated signaling section says gp130 is the signal-transducing chain shared by the listed IL-6-family cytokines. However, the source also includes IL-35, which the citing sentence omits from its apparently exhaustive list. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    IL-1β and SAA1 are crucial for muscle atrophy in sepsis and both increased mRNA and protein expression of IL-6 as well as MuRF1/Trim63 and Atrogin-1/Fbxo32.

    “Recently, we showed that IL‐1β and SAA1 are crucial for muscle atrophy in sepsis and that both increased the mRNA and protein expression of IL‐6 as well as MuRF1/Trim63 and Atrogin‐1/Fbxo32. 11 , 12 , 26”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [11] Langhans C, Weber‐Carstens S, Schmidt F, Hamati J, Kny M, Zhu X, et al. Inflammation‐induced acute phase response in skeletal muscle and critical illness myopathy. PLoS One. 2014; 9: e92048, 10.1371/journal.pone.0092048 24651840 PMC3961297 source

      The Results section reports increased SAA1 in septic mouse muscle, and the Discussion suggests that SAA1 contributes to inflammation-induced muscular atrophy. The paper does not establish that IL-1β and SAA1 are crucial for atrophy in sepsis or that both increase IL-6, MuRF1/Trim63, and Atrogin-1/Fbxo32 mRNA and protein. Instead, its experiments show IL-6 increasing SAA1 expression. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [12] Hahn A, Kny M, Pablo‐Tortola C, Todiras M, Willenbrock M, Schmidt S, et al. Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors. J Cachexia Sarcopenia Muscle 2020; 11: 103– 119. 31441598 PMC7015249 source

      The Results (page not provided) show that SAA1 increased IL-6 expression and secretion in myotubes, and the Conclusions link SAA1 to atrophy and increased MuRF1 and Atrogin-1. But the Results also report that Trim63/MuRF1 mRNA remained unchanged after SAA1 treatment, and this paper does not show that IL-1β increased all the named markers at both mRNA and protein levels. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] Haberecht‐Muller S, Kruger E, Fielitz J. Out of control: the role of the ubiquitin proteasome system in skeletal muscle during inflammation. Biomolecules 2021; 11: 1327, 10.3390/biom11091327 34572540 PMC8468834 source

      Sections 4.3 and 4.4 link IL-1β and SAA1 to muscle atrophy in sepsis and describe pathways involving MuRF1 and atrogin-1. Section 4.2 says IL-1β stimulates IL-6 production, while section 4.4 reports SAA1-induced IL6 expression in non-muscle cells. The review does not establish the more specific claim that both factors increased mRNA and protein expression of IL-6, MuRF1 and atrogin-1. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    AG490 treatment protected against liver and lung injury and improved survival in CLP-induced sepsis and LPS-induced toxic shock in mice.

    “AG490 treatment protected against liver and lung injury and improved survival in CLP‐induced sepsis and LPS‐induced toxic shock in mice. 29 , 30 , 31”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [29] Peña G, Cai B, Deitch EA, Ulloa L. JAK2 inhibition prevents innate immune responses and rescues animals from sepsis. J Mol Med (Berl) 2010; 88: 851– 859. 20393690 PMC3083634 source

      The Results report improved survival after AG490 treatment in mice with CLP-induced sepsis and in LPS-induced endotoxemia. They report reduced TNF in the lung, but not the liver; reduced TNF is not itself evidence of protection against lung injury. The Discussion says the authors did not observe organ dysfunction or liver injury, so this paper does not establish that AG490 protected against liver and lung injury. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [30] Gyurkovska V, Ivanovska N. Tyrosine kinase inhibitor tyrphostin AG490 reduces liver injury in LPS‐induced shock. Eur J Pharmacol 2015; 751: 118– 126. 25666385 source
    • cites [31] Hui L, Yao Y, Wang S, Yu Y, Dong N, Li H, et al. Inhibition of Janus kinase 2 and signal transduction and activator of transcription 3 protect against cecal ligation and puncture‐induced multiple organ damage and mortality. J Trauma 2009; 66: 859– 865. 19276765 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Treatment with ruxolitinib resulted in clinical improvements in polycythemia vera and increased survival in primary myelofibrosis.

    “Treatment with the JAK1/2 inhibitor ruxolitinib resulted in clinical improvements in polycythemia vera and an increased survival in primary myelofibrosis. 32 , 33”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] Vannucchi AM. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372: 1670– 1671. 25901432 source
    • cites [33] Verstovsek S, Gotlib J, Mesa RA, Vannucchi AM, Kiladjian JJ, Cervantes F, et al. Long‐term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT‐I and ‐II pooled analyses. J Hematol Oncol 2017; 10: 156. 28962635 PMC5622445 source

      The Results report longer overall survival with ruxolitinib than with control in patients with intermediate-2 or high-risk myelofibrosis. The Background says this population includes primary myelofibrosis, but the reported survival result is for myelofibrosis overall, not a primary-myelofibrosis subgroup. This paper does not evaluate clinical improvement in polycythemia vera; the sentence also cites another source for that part. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    gp130 via the JAK/STAT pathway mediates muscle atrophy in a cancer cachexia mouse model.

    “Our data are in accordance with previous reports showing that gp130 via the JAK/STAT pathway mediates muscle atrophy in a cancer cachexia mouse model. 15 , 27 , 28”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [15] Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge DC, Khuri S, Koniaris LG, et al. STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLoS One 2011; 6: e22538, 10.1371/journal.pone.0022538 21799891 PMC3140523 source

      The Introduction (page unavailable) describes IL-6 signaling through gp130 and JAK to activate STAT3, while the Results report muscle wasting and increased muscle STAT3 activation in C26 tumor-bearing mice. The paper supports an association and proposes a mechanism, but does not establish that the gp130–JAK/STAT pathway causally mediates the atrophy as the citing sentence states. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [27] Puppa MJ, Gao S, Narsale AA, Carson JA. Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma‐induced cachexia. FASEB J 2014; 28: 998– 1009. 24145720 PMC3898653 source
    • cites [28] Silva KA, Dong J, Dong Y, Dong Y, Schor N, Tweardy DJ, et al. Inhibition of Stat3 activation suppresses caspase‐3 and the ubiquitin‐proteasome system, leading to preservation of muscle mass in cancer cachexia. J Biol Chem 2015; 290: 11177– 11187. 25787076 PMC4409274 source

      The Abstract and Discussion (page unavailable) report that Stat3 activation contributes to muscle loss in mice with C26 or Lewis lung carcinoma tumors, and that inhibiting Stat3 preserves muscle mass. The paper does not establish that gp130 mediates this effect; gp130 appears in the title of a cited work in the References, not as a tested mediator in this study. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    STAT3 inhibition attenuated cancer-associated muscle wasting in mice bearing colon-26 carcinoma.

    “In accordance with our data, STAT3 inhibition attenuated cancer‐associated muscle wasting in mice bearing colon‐26 carcinoma. 16”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R, Puzis L, et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL‐6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab 2012; 303: E410– E421. 22669242 PMC3423125 source

  • May combine two claims.

    Findingown data

    The reduction in muscle atrophy with AG490 is accompanied by a reduction in Fbxo32/Atrogin-1 mRNA (−81.3%, P<0.05) and Trim63/MuRF1 mRNA expression (−77.6%, P<0.05) and protein content.

    “The reduction in muscle atrophy was accompanied by a reduction in Fbxo32/Atrogin‐1‐mRNA (−81.3%, P < 0.05) and Trim63/MuRF1‐mRNA expression (−77.6%, P < 0.05) and protein content.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CLP causes loss of TA muscle weight in mice, which is attenuated in Il6st-cKO mice (WT: −22.3%, cKO: −13.5%; P<0.001).

    “CLP caused a loss of TA muscle weight, which was attenuated in Il6st‐cKO mice (WT: −22.3%, P < 0.001, cKO: −13.5%, P < 0.001; WT vs. cKO P < 0.001).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.

  • May combine two claims.

    Findingown data

    CLP reduces MCSA of fast twitch/type II myofibres in TA muscle of septic WT mice, and this reduction is attenuated in septic Il6st-cKO mice (WT: −26.7%, cKO: −6.0%; P<0.001).

    “ATPase‐stained histological cross sections showed a reduction in MCSA of fast twitch/type II myofibres of septic WT mice that was attenuated in TA (WT: −26.7%, cKO: −6.0%; P < 0.001; Figure 4D–4F) and GP (WT: −39.1%, cKO: −21.5%; P < 0.001; Figure 4H–4J) of septic cKO mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.

  • May combine two claims.

    Findingown data

    CLP reduces MCSA of fast twitch/type II myofibres in GP muscle of septic WT mice, and this reduction is attenuated in septic Il6st-cKO mice (WT: −39.1%, cKO: −21.5%; P<0.001).

    “ATPase‐stained histological cross sections showed a reduction in MCSA of fast twitch/type II myofibres of septic WT mice that was attenuated in TA (WT: −26.7%, cKO: −6.0%; P < 0.001; Figure 4D–4F) and GP (WT: −39.1%, cKO: −21.5%; P < 0.001; Figure 4H–4J) of septic cKO mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.

  • May combine two claims.

    Findingown data

    RNAseq data revealed increased expression of genes involved in insulin resistance and decreased expression of genes involved in insulin signalling in skeletal muscle of septic mice.

    “Our RNAseq data revealed an increased expression of genes involved in insulin resistance and a decreased expression of genes involved in insulin signalling, suggesting that insulin resistance also occurs in skeletal muscle of septic mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-6 caused atrophy of C2C12 myotubes, which was attenuated by knockdown of Il6st/gp130 and treatment with JAK2 or STAT3 inhibitors.

    “Second, IL‐6 caused atrophy of C2C12 myotubes, which was attenuated by knockdown of Il6st/gp130 and treatment with JAK2 or STAT3 inhibitors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither sepsis nor AG490 treatment had an effect on Myh2 mRNA expression in TA or GP muscles.

    “Neither sepsis nor AG490 treatment had an effect on Myh2 mRNA expression in TA or GP muscles (Figure 5M, Figure S9F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    IL-6 promoted protein degradation and inhibited insulin signalling.

    “Fourth, IL‐6 promoted protein degradation and inhibited insulin signalling, which might reduce muscular protein synthesis and therefore protein homeostasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RNAseq data showed that expression of genes involved in IL-6 signalling were increased in muscle of septic mice, whereas expression of other IL-6 family members and their receptors was not as much increased or even reduced.

    “Our RNAseq data showed that the expression of genes involved in IL‐6 signalling were increased in muscle of septic mice, whereas the expression of the other IL‐6 family members and their receptors was not as much increased or even reduced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Skeletal muscle specific deletion of Il6st and pharmacological JAK2 inhibition by AG490 attenuated sepsis-induced muscle atrophy in mice in vivo.

    “Third, skeletal muscle specific deletion of Il6st and pharmacological JAK2 inhibition by AG490 attenuated sepsis‐induced muscle atrophy in mice in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inhibition of IL-6/gp130 signalling by IL6st-knockdown, JAK2 or STAT3 inhibition prevents IL-6-induced SOCS3 expression as well as myocyte atrophy in vitro and skeletal muscle atrophy in vivo.

    “Inhibition of IL‐6/gp130 signalling by IL6st‐knockdown (e.g. Il6st siRNA and Il6st cKO), JAK2 (e.g. AG490) or STAT3 inhibition (e.g. C188‐9 and S3i‐201) prevents IL‐6‐induced SOCS3 expression as well as myocyte atrophy in vitro and skeletal muscle atrophy in vivo (Figure 7).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    MCSA measurements were performed in a blinded fashion.

    “One hundred myocyte cross‐sectional areas (MCSAs) were measured per mouse, muscle and condition in a blinded fashion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All experiments were performed independently and at least three times using biological triplicates each.

    “All experiments were performed independently and at least three times using biological triplicates each.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In ICUAW, atrophy predominantly occurs in fast twitch/type II myofibres and is mainly mediated by the ubiquitin-proteasome system.

    “In ICUAW, atrophy predominantly occurs in fast twitch/type II myofibres 6 and is mainly mediated by the ubiquitin‐proteasome system.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Bierbrauer J, Koch S, Olbricht C, Hamati J, Lodka D, Schneider J, et al. Early type II fiber atrophy in intensive care unit patients with nonexcitable muscle membrane. Crit Care Med 2012; 40: 647– 650. 21963579 source

  • May combine two claims.

    Study design and conductown data

    At baseline, Il6st-cKO mice showed no differences in survival, body weight, and IL-6 plasma levels compared to WT.

    “At baseline, cKO mice showed no differences in survival, body weight, and IL‐6 plasma levels (Table S3, Figure S7B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.

  • May combine two claims.

    Interpretationown data

    IL-6 activates the JAK/STAT3 pathway and causes atrophy of myocytes in vitro.

    “These data indicate that IL‐6 activates the JAK/STAT3 pathway and causes atrophy of myocytes in vitro.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    IL-6 via the gp130/JAK2/STAT3 pathway mediates sepsis-induced muscle atrophy, possibly contributing to ICUAW.

    “IL‐6 via the gp130/JAK2/STAT3‐pathway mediates sepsis‐induced muscle atrophy possibly contributing to ICUAW.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.

  • May combine two claims.

    Interpretationown data

    gp130 mediates STAT3 activation and Socs3 expression in TA muscle of septic mice.

    “These data indicate that gp130 mediates STAT3 activation and Socs3 expression in TA of septic mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.

  • May combine two claims.

    Interpretationown data

    Il6st deletion prevents sepsis-induced muscle atrophy in mice, associated with a reduction of MuRF1 protein levels in cKO mice.

    “In summary, these data indicate that gp130 activates STAT3/Socs3 in muscle during sepsis and that Il6st deletion prevents sepsis‐induced muscle atrophy. This was associated with a reduction of MuRF1 protein levels in cKO mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pax7-Cre specifically deletes Il6st in myocytes.

  • May combine two claims.

    Premisecitation

    Both MuRF1 and Atrogin-1 are increased early and persistently during critical illness and possibly mediate muscle atrophy in ICUAW patients.

    “Both MuRF1 and Atrogin‐1 are increased early and persistently during critical illness and possibly mediate muscle atrophy in ICUAW patients.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Wollersheim T, Woehlecke J, Krebs M, Hamati J, Lodka D, Luther‐Schroeder A, et al. Dynamics of myosin degradation in intensive care unit‐acquired weakness during severe critical illness. Intensive Care Med 2014; 40: 528– 538. 24531339 source
    • cites [6] Bierbrauer J, Koch S, Olbricht C, Hamati J, Lodka D, Schneider J, et al. Early type II fiber atrophy in intensive care unit patients with nonexcitable muscle membrane. Crit Care Med 2012; 40: 647– 650. 21963579 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Myotube diameter measurements were performed in a blinded fashion.

    “Out of 100 myotubes per condition, three diameters per myotube were measured and averaged using the ImageJ software in a blinded fashion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Different JAK inhibitors received approval for clinical use in patients with polycythemia vera and primary myelofibrosis, in which somatic JAK2 mutations are common.

    “Indeed, different JAK inhibitors received approval for clinical use in patients with polycythemia vera and primary myelofibrosis, in which somatic JAK2 mutations are common.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    IL-6 acts on myocytes via the gp130 and IL-6Rα-complex and activates JAK2- and STAT3-signalling, leading to increased expression of SOCS3.

    “IL‐6 acts on myocytes via the gp130 and IL‐6Rα‐complex and activates JAK2‐ and STAT3‐signalling, which leads to an increased expression of SOCS3 (Figure 7).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mice devoid of Il6st in myocytes were protected from cancer cachexia, attributed to reduced Atrogin-1 expression, while MuRF1 was not analysed.

    “Mice devoid of Il6st in myocytes were protected from cancer cachexia, which was attributed to a reduced Atrogin‐1 expression, while MuRF1 was not analysed. 27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Puppa MJ, Gao S, Narsale AA, Carson JA. Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma‐induced cachexia. FASEB J 2014; 28: 998– 1009. 24145720 PMC3898653 source

  • May combine two claims.

    Interpretationreasoning

    IL-6 via the gp130/JAK2/STAT3-pathway mediates sepsis-induced muscle atrophy and possibly contributes to ICUAW.

    “In summary, IL‐6 via the gp130/JAK2/STAT3‐pathway mediates sepsis‐induced muscle atrophy and possibly contributes to ICUAW.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The CLP mouse model reproduces the key features of human sepsis-induced muscle atrophy and ICUAW.
    • Rests on an assumption: C2C12 myotubes are a valid model for studying IL-6/gp130/JAK2/STAT3 signalling in human skeletal muscle.

  • May combine two claims.

    Interpretationreasoning

    Reduction of IRS-1 is paralleled by decreased Akt-activity that results in reduced protein synthesis and increased protein degradation, which eventually mediate muscle atrophy.

    “Reduction of IRS‐1 is paralleled by a decreased Akt‐activity that results in a reduced protein synthesis and an increased protein degradation, which eventually mediate muscle atrophy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: SOCS3 inhibits the insulin/insulin-receptor/Akt pathway by degradation of IRS-1.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    It seems feasible to investigate the effects of JAK inhibitors in septic patients.

    “Because of the good tolerability of JAK inhibitors and the improved outcomes of JAK inhibitor‐treated septic mice, it seems feasible to investigate their effects in septic patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The anti-atrophic effects of AG490 are not only mediated by inhibition of muscular gp130 signalling but also by its systemic anti-inflammatory effect.

    “Therefore, we suggest that the anti‐atrophic effects of AG490 are not only mediated by inhibition of muscular gp130 signalling but also by its systemic anti‐inflammatory effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study used only male mice for the experiments.

    “Because, we have used only male mice for our experiments, further sex‐specific studies are needed to elucidate if IL‐6 signalling is equally important for sepsis‐induced muscle atrophy in female mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    AG490 treatment decreased IL-6 and IL-12 plasma levels and decreased numbers of T-cells and monocytes in peritoneal lavage of mice with LPS-induced toxic shock.

    “In addition, Gyurkovska and Ivanovska found decreased IL‐6 and IL‐12 plasma levels as well as decreased numbers of T‐cells and monocytes in the peritoneal lavage of AG490 treated mice with LPS‐induced toxic shock. 30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Gyurkovska V, Ivanovska N. Tyrosine kinase inhibitor tyrphostin AG490 reduces liver injury in LPS‐induced shock. Eur J Pharmacol 2015; 751: 118– 126. 25666385 source

  • May combine two claims.

    Interpretationown data

    IL-6 does not increase Trim63 expression, but possibly increases its translation or its protein stability, or reduces its degradation.

    “Our data implicate that IL‐6 does not increase Trim63 expression, but possibly increases its translation or its protein stability, or reduces its degradation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Inhibition of this pathway in muscle could be beneficial to prevent sepsis-induced muscle wasting.

    “An inhibition of this pathway in muscle could be beneficial to prevent sepsis‐induced muscle wasting.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study used 12-20-week-old mice, which relates to a young age in human patients.

    “Here, we have used 12–20‐week‐old mice, which relates to a young age in human patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    IL-6 inhibits insulin signalling, suggesting that IL-6-induced atrophy is mediated by both increased protein degradation and decreased protein synthesis.

    “These data indicate that IL‐6 inhibits insulin signalling, suggesting that IL‐6‐induced atrophy is mediated by both an increased protein degradation and a decreased protein synthesis.”
    Quote in the paperSubstantial claim
46 of 46

  • The paper relies on this without support.

    The role of IL-6 signalling in sepsis-induced muscle atrophy is not well understood.

    “However, the role of IL‐6 signalling in sepsis‐induced muscle atrophy is not well understood.”

  • The paper relies on this without support.

    Pax7-Cre specifically deletes Il6st in myocytes.

    “Il6st loxP/loxP mice were crossed with Cre carrying mice controlled by myoblast‐specific Pax7‐promotor (Pax7‐Cre) (cKO, Il6stloxP/loxP; Pax7‐Cre).”

  • The paper relies on this without support.

    The CLP mouse model reproduces the key features of human sepsis-induced muscle atrophy and ICUAW.

    “In summary, IL‐6 via the gp130/JAK2/STAT3‐pathway mediates sepsis‐induced muscle atrophy and possibly contributes to ICUAW.”

  • The paper relies on this without support.

    C2C12 myotubes are a valid model for studying IL-6/gp130/JAK2/STAT3 signalling in human skeletal muscle.

    “Our in vitro experiments were performed in murine C2C12 myotubes. Further analyses of primary murine and/or human myocytes are needed to independently confirm our observations about the role of IL‐6/gp130/JAK2/STAT3 signalling in myocyte atrophy in vitro.”

  • The paper relies on this without support.

    SOCS3 inhibits the insulin/insulin-receptor/Akt pathway by degradation of IRS-1.

    “SOCS3 functions as a negative regulator of cytokine signalling and inhibits the growth promoting insulin/insulin‐receptor/Akt pathway by degradation of IRS‐1.”

  • The paper relies on this without support.

    AG490 specifically inhibits JAK2.

    “The JAK2 inhibitor AG490 attenuated sepsis‐induced muscle atrophy in vitro and in vivo.”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Patient sample sizes disagree

    Major

    The Methods say muscle biopsies were analysed from five critically ill patients, but the Figure 1 caption reports 25 patients on Day 5 and 19 on Day 15 for the SOCS3 analysis.

  • AG490 experiment uses conflicting mouse descriptions

    Major

    The Methods describe the AG490 experiment as using 20-week-old C57BL/6J mice, whereas the Figure 5 caption describes 12- to 16-week-old Il6st cKO and WT mice for that experiment.

  • Figure 4A is assigned conflicting time points

    Minor

    The Results cite Figure 4A as showing MuRF1 protein levels after 96 hours, but the Figure 4 caption assigns its Western blot analyses to the 24-hour time point.

3 of 3

Cites

Flagged first, then by citations

1 of the 41 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Zanders, L., Kny, M., Hahn, A., Schmidt, S., Wundersitz, S., Todiras, M., Lahmann, I., Bandyopadhyay, A., Wollersheim, T., Kaderali, L., Luft, F. C., Birchmeier, C., Weber‐Carstens, S., & Fielitz, J.
Affiliations
  • Max Delbrück Center (DE)
  • Cardiovascular hormones, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association Berlin Germany
  • Universitätsmedizin Greifswald (DE)
  • Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
Corresponding author
Fielitz, Jens
ORCID
Venue
Journal of Cachexia, Sarcopenia and Muscle
Publisher
Wiley
Published
2021-11-24
Volume
13
Issue
1
Pages
713-727
ISSN
  • 2190-5991 (ISSN-L)
  • 2190-6009
DOI
10.1002/jcsm.12867
PMC
PMC8818599
OpenAlex
W3215680661
Semantic Scholar
bbcf2c8c3e50339c2dd2da842d1f034533acd3f2
Cited by
225
References
41
Citations by year
2026: 46 · 2025: 71 · 2024: 46 · 2023: 45 · 2022: 15 · 2021: 1 · 2020: 1
FWCI
7.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cachexia Sarcopenia and Muscle (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Berlin Institute of Health
  • Deutsche Forschungsgemeinschaft (FI 965/9‐1, FI 965/5‐2, FI 965/5‐1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords
sepsis, ICU-acquired weakness, muscle atrophy, interleukin-6, gp130, SOCS3, skeletal muscle, cecal ligation and puncture, JAK2 inhibition, STAT3 inhibition, myotube atrophy, inflammation, tibialis anterior
MeSH terms
Animals, Humans, Muscular Atrophy, Interleukin-6, Muscle, Skeletal, Sepsis, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Janus Kinase 2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

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