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

Uta Barbara Metzing,Christian Von Loeffelholz,Christian Kosan,Andreas L Birkenfeld,René Winkler,Falk Rauchfuß,Christian Stoppe,Ralf A Claus,Martin O Weickert,Sina M Coldewey,Claudia Weinmann,Paul Horn,Ricardo Steidl,Bernd Romeike,Utz Settmacher

doi:10.1038/s41598-021-04517-9

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.

Highlights

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 suffering from sepsis had increased homeostasis model assessment of insulin resistance (HOMA-IR), comparable to insulin-resistant subjects, and possibly reflecting both acute insulin resistance and inclusion of five patients (38%) with pre-existing type 2 diabetes (T2D)
We provide novel findings showing that peritoneal sepsis, in humans and mice, is related to skeletal muscle macrophage infiltration and local activation of the unfolded protein response

Summary

Introduction

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. Perturbations of ER homeostasis by inflammation or metabolic stress can induce cellular protein trafficking, resulting in a rise of folding defects and can provoke a condition called ER s tress[8]. This initiates the activation of defined signaling cascades, namely the unfolded protein response (UPR)[8]. We aimed to provide first in human data for the regulation of the UPR in skeletal muscle of septic patients and compare these findings to a complementary animal model

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