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Critical Care

, 15:R233

First Online: 29 September 2011Received: 01 March 2011Revised: 19 August 2011Accepted: 29 September 2011

Abstract

IntroductionICU-acquired muscle weakness commonly occurs in patients with septic shock and is associated with poor outcome. Although atrophy is known to be involved, it is unclear whether ligands in plasma from these patients are responsible for initiating degradation of muscle proteins. The aim of the present study was to investigate if plasma from septic shock patients induces skeletal muscle atrophy and to examine the time course of plasma-induced muscle atrophy during ICU stay.

MethodsPlasma was derived from septic shock patients within 24 hours after hospital admission n = 21 and healthy controls n = 12. From nine patients with septic shock plasma was additionally derived at two, five and seven days after ICU admission. These plasma samples were added to skeletal myotubes, cultured from murine myoblasts. After incubation for 24 hours, myotubes were harvested and analyzed on myosin content, mRNA expression of E3-ligase and Nuclear Factor Kappa B NFκB activity. Plasma samples were analyzed on cytokine concentrations.

ResultsMyosin content was approximately 25% lower in myotubes exposed to plasma from septic shock patients than in myotubes exposed to plasma from controls P < 0.01. Furthermore, patient plasma increased expression of E3-ligases Muscle RING Finger protein-1 MuRF-1 and Muscle Atrophy F-box protein MAFbx P < 0.01, enhanced NFκB activity P < 0.05 and elevated levels of ubiquitinated myosin in myotubes. Myosin loss was significantly associated with elevated plasma levels of interleukin IL-6 in septic shock patients P < 0.001. Addition of antiIL-6 to septic shock plasma diminished the loss of myosin in exposed myotubes by approximately 25% P < 0.05. Patient plasma obtained later during ICU stay did not significantly reduce myosin content compared to controls.

ConclusionsPlasma from patients with septic shock induces loss of myosin and activates key regulators of proteolysis in skeletal myotubes. IL-6 is an important player in sepsis-induced muscle atrophy in this model. The potential to induce atrophy is strongest in plasma obtained during the early phase of human sepsis.

AbbreviationsDMEMDulbecco-s Modified Eagle-s Medium

EMSAelectrophoretic mobility shift assay

ICUintensive care unit

IFN-γinterferon gamma

IL-1βinterleukin 1 beta

IL-6interleukin 6

MAFbxmuscle atrophy F-box protein

MuRF-1muscle RING finger protein-1

NFκBnuclear factor Kappa B

TNF-αtumor necrosis factor alpha.

Electronic supplementary materialThe online version of this article doi:10.1186-cc10475 contains supplementary material, which is available to authorized users.

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Autor: Hieronymus WH van Hees - Willem-Jan M Schellekens - Marianne Linkels - Floris Leenders - Jan Zoll - Rogier Donders - PN R

Fuente: https://link.springer.com/



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