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Cited by 101Intensive Care Unit Cognitive DisordersSepsis Diagnosis and TreatmentMuscle Physiology and Disorders

Inflammation-Induced Acute Phase Response in Skeletal Muscle and Critical Illness Myopathy

Open access
Langhans, Claudia, Weber-Carstens, Steffen, Schmidt, Franziska, Hamati, Jida, Kny, Melanie, Zhu, Xiaoxi, Wollersheim, Tobias, Koch, Susanne +14 more·2014·PLoS ONE
DOI 10.1371/journal.pone.0092048PMC PMC3961297
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Abstract

OBJECTIVES: Systemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM. DESIGN: Prospective observational clinical study and prospective animal trial. SETTING: Two intensive care units (ICU) and research laboratory. PATIENTS/SUBJECTS: 33 patients with Sequential Organ Failure Assessment scores ≥ 8 on 3 consecutive days within 5 days in ICU were investigated. A subgroup analysis of 12 patients with, and 18 patients without CIM (non-CIM) was performed. Two consecutive biopsies from vastus lateralis were obtained at median days 5 and 15, early and late time points. Controls were 5 healthy subjects undergoing elective orthopedic surgery. A septic mouse model and cultured myoblasts were used for mechanistic analyses. MEASUREMENTS AND MAIN RESULTS: Early SAA1 expression was significantly higher in skeletal muscle of CIM compared to non-CIM patients. Immunohistochemistry showed SAA1 accumulations in muscle of CIM patients at the early time point, which resolved later. SAA1 expression was induced by IL-6 and tumor necrosis factor-alpha in human and mouse myocytes in vitro. Inflammation-induced muscular SAA1 accumulation was reproduced in a sepsis mouse model. CONCLUSIONS: Skeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis. TRIAL REGISTRATION: ISRCTN77569430.

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  • 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 [11]

    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

  • 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 [11]

    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

  • 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 [11]

    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)

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Authors
Langhans, C., Weber-Carstens, S., Schmidt, F., Hamati, J., Kny, M., Zhu, X., Wollersheim, T., Koch, S., Krebs, M., Schulz, H., Lodka, D., Saar, K., Labeit, S., Spies, C., Hubner, N., Spranger, J., Spuler, S., Boschmann, M., Dittmar, G., Butler-Browne, G., Mouly, V., & Fielitz, J.
Affiliations
  • Max Delbrück Center (DE)
  • Charité – Universitätsmedizin Berlin (DE)
  • University of Mannheim (DE)
  • Inserm (FR)
Corresponding author
Fielitz, Jens
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-03-20
Volume
9
Issue
3
Pages
e92048
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0092048
PMC
PMC3961297
OpenAlex
W2050700956
Cited by
101
References
3
Citations by year
2026: 6 · 2025: 8 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 12 · 2020: 12 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 8 · 2014: 3
FWCI
6.47
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Muscular Dystrophy Association
  • Deutsche Forschungsgemeinschaft (FI 965/2-1, 965/2-1, FI 965/4-1, GK 1631, KFO-192, /14-1, 965/4-1)
Topics
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Intensive Care Unit Cognitive Disorders
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
critical illness myopathy, systemic inflammation, acute phase response, skeletal muscle, serum amyloid A1, interleukin-6, TNF-α, sepsis, myoblasts, intensive care unit patients
MeSH terms
Acute-Phase Reaction, Adult, Serum Amyloid A Protein, Animals, Female, Gene Expression Regulation, Humans, Inflammation, Lipopolysaccharides, Male, Membranes, Middle Aged, Muscular Diseases, Tumor Necrosis Factor-alpha, Interleukin-6, Case-Control Studies, Critical Illness, Muscle, Skeletal, Sepsis, Inflammation Mediators, Oligonucleotide Array Sequence Analysis, Mice

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