Endoplasmic reticulum stress and the unfolded protein response in skeletal muscle of subjects suffering from peritoneal sepsis

• Published in: Scientific reports Vol. 12; no. 1; pp. 504 - 11
• Main Authors: Metzing, Uta Barbara, von Loeffelholz, Christian, Steidl, Ricardo, Romeike, Bernd, Winkler, René, Rauchfuß, Falk, Settmacher, Utz, Stoppe, Christian, Coldewey, Sina M., Weinmann, Claudia, Weickert, Martin O., Claus, Ralf A., Birkenfeld, Andreas L., Kosan, Christian, Horn, Paul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250; 631/250/255; 692/4017; 692/699; Aged; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - metabolism; Bcl-2 protein; Bcl-x protein; Cell death; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Female; GADD34 protein; Humanities and Social Sciences; Humans; Inflammation; Inositol; Male; Mice; Mice, Inbred C57BL; Middle Aged; mRNA; multidisciplinary; Muscle, Skeletal - metabolism; Musculoskeletal system; Patients; Peritoneal Diseases - genetics; Peritoneal Diseases - metabolism; Peritoneal Diseases - physiopathology; Peritoneum; Protein folding; Protein Phosphatase 1 - genetics; Protein Phosphatase 1 - metabolism; Proteins; Science; Science (multidisciplinary); Sepsis; Sepsis - genetics; Sepsis - metabolism; Sepsis - physiopathology; Skeletal muscle; Unfolded Protein Response; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-04517-9

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.