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Cited by 67Muscle Physiology and DisordersIntensive Care Unit Cognitive DisordersSepsis Diagnosis and Treatment

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

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Hahn, Alexander, Kny, Melanie, Pablo‐Tortola, Cristina, Todiras, Mihail, Willenbrock, Michael, Schmidt, Sibylle, Schmoeckel, Katrin, Jorde, Ilka +10 more·2020·Journal of Cachexia, Sarcopenia and Muscle
DOI 10.1002/jcsm.12491PMC PMC7015249
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Abstract

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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  • 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).”

    From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [12]

    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

  • 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.”

    From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [12]

    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

  • 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”

    From Sepsis induces interleukin 6, gp130/JAK2/STAT3, and muscle wasting (2022) · cites this paper as [12]

    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

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

    Zanders, L., Kny, M., Hahn, A., Schmidt, S., Wundersitz, S., Todiras, M., Lahmann, I., Bandyopadhyay, A., Wollersheim, T., Kaderali, L., et al. (2022) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12867 · Cited by 225 · see citing works

    “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) Together with our novel data, we 720 L.”
    BackgroundSelf-citation

Authors
Hahn, A., Kny, M., Pablo‐Tortola, C., Todiras, M., Willenbrock, M., Schmidt, S., Schmoeckel, K., Jorde, I., Nowak, M., Jarosch, E., Sommer, T., Bröker, B. M., Felix, S. B., Scheidereit, C., Weber‐Carstens, S., Butter, C., Luft, F. C., & Fielitz, J.
Affiliations
  • Max Delbrück Center (DE)
  • Experimental and Clinical Research Center, Charité‐Universitätsmedizin Berlin Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany
  • Cardiovascular hormones Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany
  • Universitätsmedizin Greifswald (DE)
  • Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
  • Immanuel Klinikum Bernau (DE)
Corresponding author
Fielitz, Jens
ORCID
Venue
Journal of Cachexia, Sarcopenia and Muscle
Publisher
Wiley
Published
2019-08-23
Volume
11
Issue
1
Pages
103-119
ISSN
  • 2190-5991 (ISSN-L)
  • 2190-6009
DOI
10.1002/jcsm.12491
PMC
PMC7015249
OpenAlex
W2969976316
Cited by
67
References
9
Citations by year
2026: 7 · 2025: 9 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 14 · 2020: 6
FWCI
2.56
Type
journal article
Language
en
Open access
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Locations
  • Journal of Cachexia Sarcopenia and Muscle (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
Deutsche Forschungsgemeinschaft (FI 965/5‐2, FI 965/5‐1, FI 965/4‐1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Intensive Care Unit Cognitive Disorders
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords
serum amyloid A1, muscle atrophy, ICU-acquired weakness, TLR2, TLR4, NF-κB signaling, sepsis, acute phase response, systemic inflammation, polymicrobial sepsis, cecal ligation and puncture, BMS-345541, interleukin-6, myotubes
MeSH terms
Serum Amyloid A Protein, Animals, Disease Models, Animal, Humans, Male, Muscular Atrophy, Muscle, Skeletal, Muscle Fibers, Skeletal, Toll-Like Receptors, Mice

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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