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

Claudia Langhans, Steffen Weber-Carstens, Franziska Schmidt, Jida Hamati, Melanie Kny, Xiaoxi Zhu, Tobias Wollersheim, Susanne Koch, Martin Krebs, Herbert Schulz, Doerte Lodka, Kathrin Saar, Siegfried Labeit, Claudia Spies, Norbert Hubner, Joachim Spranger, Simone Spuler, Michael Boschmann, Gunnar Dittmar, Gillian Butler-BrowneVincent Mouly, Jens Fielitz

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53 Citations (Scopus)

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.

Original languageEnglish
Article numbere92048
JournalPLoS ONE
Volume9
Issue number3
DOIs
Publication statusPublished - 20 Mar 2014
Externally publishedYes

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