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

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

doi:10.1371/journal.pone.0092048

Abstract

ObjectivesSystemic 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.DesignProspective observational clinical study and prospective animal trial.SettingTwo intensive care units (ICU) and research laboratory.Patients/Subjects33 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 ResultsEarly 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.ConclusionsSkeletal muscle contributes to general inflammation and acute-phase response in CIM patients. Muscular SAA1 could be important for CIM pathogenesis.Trial RegistrationISRCTN77569430.

Highlights

Intensive care unit (ICU)-acquired weakness is a serious complication during critical illness, characterized by loss of muscle mass, preferential atrophy of fast-twitch myofibers and weakness [1,2,3]
Skeletal muscle contributes to general inflammation and acute-phase response in critical illness myopathy (CIM) patients
Among these we found serum amyloid A 1 and 4 (SAA1, SAA4) and reasoned that acute phase response occurred in muscle during critical illness, especially in CIM patients

Summary

Introduction

Intensive care unit (ICU)-acquired weakness is a serious complication during critical illness, characterized by loss of muscle mass, preferential atrophy of fast-twitch myofibers and weakness [1,2,3]. The clinical consequences are prolonged hospital stay and mechanical ventilation, increased hospital mortality, and chronic physical disability [4,5]. Others and we recently reported that non-excitable muscle membranes indicate patients at risk for critical illness myopathy (CIM) early during the disease process [1,7,8]. CIM deteriorates the disease course and leads to protracted rehabilitation, poor quality-of-life outcomes, and permanent disability [4,5,9]. The suffering and economic impact for the health care system and the society are high [10]

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