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Abstract
We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining. CD68 mRNA increased with sepsis in skeletal muscle of patients and animals (p < 0.05). Mainly the inositol-requiring enzyme 1α branch of the UPR was upregulated as shown by elevated X-box binding-protein 1 (XBP1u) and its spliced isoform (XBP1s) mRNA (p < 0.05, respectively). Increased expression of Gadd34 indicated activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) branch of the UPR, and was only observed in mice (p < 0.001) but not human study subjects. Selected cell death signals were upregulated in human and murine muscle, demonstrated by increased bcl-2 associated X protein mRNA and TUNEL staining (p < 0.05). In conclusion we provide a first characterization of the UPR in skeletal muscle in human sepsis.
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1 Jena University Hospital, Friedrich Schiller University, Department of Trauma, Hand and Reconstructive Surgery, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224)
2 Jena University Hospital, Friedrich Schiller University, Department of Anesthesiology and Intensive Care, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224)
3 Jena University Hospital, Friedrich Schiller University, Department of Anesthesiology and Intensive Care, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224); Bundeswehrkrankenhaus Berlin, Department of Anaesthesiology, Intensive Care, Pain Medicine and Emergency Medicine, Berlin, Germany (GRID:grid.275559.9)
4 Jena University Hospital, Section of Neuropathology, Department of Pathology, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224); University Rostock Medical Center, Dean’s Office, Medical Didactics, Rostock, Germany (GRID:grid.413108.f) (ISNI:0000 0000 9737 0454)
5 Friedrich-Schiller-University Jena, Department of Biochemistry, Center for Molecular Biomedicine (CMB), Jena, Germany (GRID:grid.9613.d) (ISNI:0000 0001 1939 2794)
6 Jena University Hospital, Department of General, Visceral and Vascular Surgery, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224)
7 University Hospital, Department of Anesthesiology and Intensive Care Medicine Wuerzburg, Wuerzburg, Germany (GRID:grid.411760.5) (ISNI:0000 0001 1378 7891); 3CARE-Cardiovascular Critical Care & Anesthesia Evaluation and Research, Medical Faculty RWTH Aachen, Aachen, Germany (GRID:grid.1957.a) (ISNI:0000 0001 0728 696X)
8 Jena University Hospital, Friedrich Schiller University, Department of Anesthesiology and Intensive Care, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224); Jena University Hospital, Septomics Research Centre, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224); Jena University Hospital, Center for Sepsis Control and Care, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224)
9 University Hospitals Coventry and Warwickshire NHS Trust, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, Coventry, UK (GRID:grid.15628.38) (ISNI:0000 0004 0393 1193); University of Warwick, Translational and Experimental Medicine, Division of Biomedical Sciences, Warwick Medical School, Coventry, UK (GRID:grid.7372.1) (ISNI:0000 0000 8809 1613); Coventry University, Centre of Applied Biological and Exercise Sciences, Faculty of Health and Life Sciences, Coventry, UK (GRID:grid.8096.7) (ISNI:0000000106754565)
10 University Hospital Tübingen, Eberhard Karls University Tübingen, Department of Diabetology Endocrinology and Nephrology, Internal Medicine IV, Tübingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249); Eberhard Karls University Tübingen, Division of Translational Diabetology, Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, Tübingen, Germany (GRID:grid.10392.39) (ISNI:0000 0001 2190 1447); Kings College London, Department of Diabetes, School of Life Course Science and Medicine, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764)
11 Jena University Hospital, Center for Sepsis Control and Care, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224); Jena University Hospital, Department of Internal Medicine IV, Gastroenterology, Hepatology and Infectious Diseases, Jena, Germany (GRID:grid.275559.9) (ISNI:0000 0000 8517 6224)