Endoplasmic reticulum stress and the unfolded protein response in skeletal muscle of subjects suffering from peritoneal sepsis: Data from a cross-sectional and experimental study
Abstract
Objective Sepsis is a life-threatening organ dysfunction mediated by host response to major inflammation. Sepsis can affect al organs including skeletal muscle. Disconcertion of endoplasmic reticulum (ER) homeostasis by cellular stressors such as inflammation results in defective protein folding. This process elicits ER stress with subsequent induction of the unfolded protein response (UPR), capable of restoring protein folding, while inducing apoptosis under conditions of unresolvable stress. However, whether ER stress is present in human sepsis-induced myopathy remains unclear. We aimed at providing a first characterization of the UPR in human septic skeletal muscle. Design Cross-sectional and experimental study. Setting Surgical ICU of Jena University Hospital. Patients/subjects Surgical controls, insulin-resistant and sepsis patients. Confirmatory animal study in male C57BL/6J mice. Interventions Blood and skeletal muscle samples were taken from patients and mice. In a complementary study, sepsis was induced by peritoneal contamination in male C57BL/6J and compared to normal and insulin-resistant mice samples. Measurements and main results Key markers of the UPR were evaluated by real-time PCR and histochemical staining methods. With sepsis, we found increased skeletal muscle inflammation as represented by elevated chemokine C-C motif ligand 2 and cluster of differentiation 68 mRNA in humans and animals (p < 0.05). Mainly the inositol-requiring enzyme 1α branch of the UPR was up regulated in sepsis as shown by increased X-box binding-protein 1 (XBP1u) and its transcriptionally active spliced isoform (XBP1s) in humans and mice (p < 0.05, respectively). Additionally, we found activation of the double-stranded RNA-dependent protein kinase (PERK) branch of the UPR (p < 0.001) in septic mice. Pro-apoptotic signals were up regulated in both, septic human and murine muscle as demonstrated by increased bcl-2 associated X protein (p < 0.05). Conclusions For the first time we provide data on activation of the UPR in septic skeletal muscle accompanied by pro-apoptotic signalling. Trial registration INSIGHT study (German Clinical Trials Register, DRKS00005450) Publication History Publication Date: 16 June 2020 (online) © Georg Thieme Verlag KG Stuttgart · New York
Authors 11
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Affiliation as printed
Universitätsklinikum Jena, Klinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie
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Friedrich Schiller University Jena
Affiliation as printed
Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich-Schiller-Universität Jena
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Affiliation as printed
Universitätsklinikum Jena, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
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Affiliation as printed
Universitätsklinikum Jena, Klinik für Unfall- und Wiederherstellungschirurgie
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Affiliation as printed
Universitätsklinikum Jena, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
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Affiliation as printed
Uniklinik RWTH Aachen, Abteilung für Intensivmedizin
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Affiliation as printed
Universitätsklinikum Jena, Klinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie
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Affiliation as printed
Universitätsklinikum Jena, Klinik für Anästhesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie
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Technische Universität Dresden · University Hospital Carl Gustav Carus
Affiliation as printed
Universitätsklinikum Carl Gustav Carus der TU Dresden, Section of Metabolic and Vascular Medicine, Medical Clinic III
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Friedrich Schiller University Jena
Affiliation as printed
Friedrich Schiller Universität Jena, Department of Biochemistry, Center for Molecular Biomedicine (CMB)
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Affiliation as printed
Universitätsklinikum Jena, Department of Internal Medicine IV, Gastroenterology, Hepatology and Infectious Diseases
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