Journal
PLOS ONE
Volume 9, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0092048
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Funding
- Deutsche forschungsgemeinschaft [FI 965/2-1, FI 965/4-1, La668/14-1]
- MyoGrad (Deutsche Forschungsgemeinschaft) [GK1631]
- Universite Franco-Allemand [CDFA-06-11]
- Muscular Dystrophy Association
- Marie Curie International Reintegration grant
- Deutsche Gesellschaft fur Muskelkranke e. V.
- [KFO 192]
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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.
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