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Inflammation-induced acute phase response in skeletal muscle and critical illness myopathy

Authors

  • C. Langhans
  • S. Weber-Carstens
  • F. Schmidt
  • J. Hamati
  • M. Kny
  • X. Zhu
  • T. Wollersheim
  • S. Koch
  • M. Krebs
  • H. Schulz
  • D. Lodka
  • K. Saar
  • S. Labeit
  • C. Spies
  • N. Hubner
  • J. Spranger
  • S. Spuler
  • M. Boschmann
  • G. Dittmar
  • G. Butler-Browne
  • V. Mouly
  • J. Fielitz

Journal

  • PLoS ONE

Citation

  • PLoS ONE 9 (3): e92048

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.


DOI

doi:10.1371/journal.pone.0092048