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

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.

Tidy up - The unfolded protein response in sepsis

“…This was associated with increased mRNA levels of the chemokine CCL2 and the receptor CD68 —a marker for macrophage infiltration in response to skeletal injury. In line with these findings, mice subjected to CLP also showed a higher expression of Xbp1 in muscle tissues, but in contrast to humans, also of Atf4 , and BiP ( 142 ). Of note, other animal studies had shown that ER stress and UPR counteract cancer-associated muscle wasting ( 147 ).…”

“…Regarding the UPR, it was shown that patients with peritoneal sepsis had a higher expression of XBP1 , but not of ATF4 or ATF6 in the muscle ( 142 ). This was associated with increased mRNA levels of the chemokine CCL2 and the receptor CD68 —a marker for macrophage infiltration in response to skeletal injury.…”

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

“…However, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) can also activate the ISR. According to the results described in the literature [ 42 , 43 , 44 ], we demonstrated that the LPS injection promotes the expression of ER stress-related genes by activating transcription factors 6 and 4 (ATF6 and ATF4), which promotes the transcription of genes involved in the ER quality control and apoptosis, respectively.…”

Incomplete autophagy: Trouble is a friend

“…The ER is pivotal to the maintenance of cellular homeostasis. 137 Studies have shown that ER stress is frequently an initiating factor for incomplete autophagy (Table 1). ER stress could disturb the intracellular ion levels, 60 which affects lysosomal enzyme activity and lysosomal acidity.…”

“…There are extensive crosstalks between above signals in the process of incomplete autophagy (Figures 3 and 4). The ER is pivotal to the maintenance of cellular homeostasis 137 . Studies have shown that ER stress is frequently an initiating factor for incomplete autophagy (Table 1).…”