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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.

SUBMITTER: Metzing UB

PROVIDER: S-EPMC8752775 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle.

Project description:Endoplasmic reticulum stress has been linked to insulin resistance in multiple tissues but the role of endoplasmic reticulum stress in skeletal muscle has not been explored. Endoplasmic reticulum stress has been reported to increase tribbles 3 expression in multiple cell lines. Here, we report that high-fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases tribbles 3 and endoplasmic reticulum stress markers in skeletal muscle. Overexpression of tribbles 3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signalling. Incubation of C2C12 cells and mouse skeletal muscle with endoplasmic reticulum stressors thapsigargin and tunicamycin increases tribbles 3 and impairs insulin signalling and glucose uptake, effects reversed in cells overexpressing RNAi for tribbles 3 and in muscles from tribbles 3 knockout mice. Furthermore, tribbles 3 knockout mice are protected from high-fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle.

| S-EPMC3707125 | biostudies-literature

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR)

Project description:We are currently studying how these information-carrying oligosaccharides are involved in cellular stress responses, particularly in human genetic diseases called Congenital Disorders Of Glycosylation in which oligosaccharide assembly is defective. We are interested in endoplasmic stress responses/unfolded protein responses. ER glycans and ER lectins are intimately involved in the folding of ER proteins. Therefore, ER lectins and ER glycosyltransferases may be controlled by these stress responses, to produce and/or recognize key glycans in the stress response. Our model system is the human dermal fibroblast. We have successfully calibrated the ER stress responses in these cells by determining the magnitudes of various stress effects (such as chaperone transcription) with different forms of ER stress. We are also completing a study in which activation the signaling molecules Ire1 and ATF6 are also calibrated. We prepared multiple identical aliquots of RNA from cells stressed under several of these calibrated conditions. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR): Study of the role of ER stress in the expression of genes for ER transferases and lectins that participate in ER folding and quality control using human skin fibroblasts. The UPR response in these cells has been calibrated using various readouts in response to different stresses: 1) 40 nM L-azetidine-2-carboxylate (AZC) 1 hour, 2) 0.2 mg/ml castanospermine, 24 hours, 3) 2 mM Dithiothreitol (DTT), 20 minutes, 4) 100nm Thapsigargin (TG), 30 minutes, 5) 5 ug/ml tunicamycin, 5 hours, 6) untreated control cells

2011-02-17 | E-GEOD-27349 | biostudies-arrayexpress

Endoplasmic reticulum stress sensing in the unfolded protein response.

Project description:Secretory and transmembrane proteins enter the endoplasmic reticulum (ER) as unfolded proteins and exit as either folded proteins in transit to their target organelles or as misfolded proteins targeted for degradation. The unfolded protein response (UPR) maintains the protein-folding homeostasis within the ER, ensuring that the protein-folding capacity of the ER meets the load of client proteins. Activation of the UPR depends on three ER stress sensor proteins, Ire1, PERK, and ATF6. Although the consequences of activation are well understood, how these sensors detect ER stress remains unclear. Recent evidence suggests that yeast Ire1 directly binds to unfolded proteins, which induces its oligomerization and activation. BiP dissociation from Ire1 regulates this oligomeric equilibrium, ultimately modulating Ire1's sensitivity and duration of activation. The mechanistic principles of ER stress sensing are the focus of this review.

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Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells.

Project description:Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation and mitochondrial abnormalities; and is postulated as a potential mechanism involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study investigates the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using the ER stress inducer tunicamycin (24 h) in the presence or absence of a superoxide dismutase/catalase mimetic Eukarion (EUK)-134. Tunicamycin induced maladaptive ER stress, which was mitigated by EUK-134 at the transcriptional level. ER stress promoted mitochondrial dysfunction, described by substantial loss of mitochondrial membrane potential, as well as a reduction in respiratory control ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated by EUK-134. Tunicamycin induced ROS-mediated biogenesis and fusion of mitochondria, which, however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of fission-related markers. Increased cellular ROS generation was observed under ER stress that was prevented by EUK-134, even though no changes in mitochondrial superoxide were noticeable. These findings suggest that targeting ROS generation using EUK-134 can amend aspects of ER stress-induced changes in mitochondrial dynamics and function, and therefore, in instances of chronic ER stress, such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness and dysfunction.

| S-EPMC7466046 | biostudies-literature

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases.

Project description:The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1? (IRE1?) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.

| S-EPMC7503386 | biostudies-literature

Endoplasmic Reticulum Stress and Unfolded Protein Response in Vernal Keratoconjunctivitis.

Project description:PurposeVernal keratoconjunctivitis (VKC) is an ocular allergic disease characterized by a type 2 inflammation, tissue remodeling, and low quality of life for the affected patients. We investigated the involvement of endoplasmic reticulum (ER) stress and unfolded protein response in VKC.MethodsConjunctival imprints from VKC patients and normal subjects (CTs) were collected, and RNA was isolated, reverse transcribed, and analyzed with the Affymetrix microarray. Differentially expressed genes between VKC patients and CTs were evaluated. Genes related to ER stress, apoptosis, and autophagy were further considered. VKC and CT conjunctival biopsies were analyzed by immunohistochemistry (IHC) with specific antibodies against unfolded protein response (UPR), apoptosis, and inflammation. Conjunctival fibroblast and epithelial cell cultures were exposed to the conditioned medium of activated U937 monocytes and analyzed by quantitative PCR for the expression of UPR, apoptosis, autophagy, and inflammatory markers.ResultsER chaperones HSPA5 (GRP78/BiP) and HYOU1 (GRP170) were upregulated in VKC patients compared to CTs. Genes encoding for ER transmembrane proteins, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), ER-associated degradation (ERAD), and autophagy were upregulated, but not those related to apoptosis. Increased positive reactivity of BiP and ATF6 and unchanged expression of apoptosis markers were confirmed by IHC. Cell cultures in stress conditions showed an overexpression of UPR, proinflammatory, apoptosis, and autophagy markers.ConclusionsA significant overexpression of genes encoding for ER stress, UPR, and pro-inflammatory pathway components was reported for VKC. Even though these pathways may lead to ER homeostasis, apoptosis, or inflammation, ER stress in VKC may predominantly contribute to promote inflammation.

| S-EPMC11008754 | biostudies-literature

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR)

2011-02-17 | GSE27349 | GEO

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade.

Project description:Multiple vaginal delivery (MVD) is an important factor for pelvic floor muscle (PFM) function decline and pelvic floor dysfunction (PFD). PFD is common in middle-aged and elderly women, but its pathogenesis is not clear. In this study, we found that the expression of CACNA1H was lower in the PFM of old mice after MVD compared with old or adult mice. In in-vitro studies, we found that treatment with the T-type Ca2+ channel (T-channel) inhibitor NNC-55 or downregulation of the CACNA1H gene by siRNA intervention promoted myotube atrophy and apoptosis. Mechanistically, we revealed that NNC-55 increased the expression of GRP78 and DDIT3 in myotubes, indicating endoplasmic reticulum stress (ERS) activation, and that the IRE1 and PERK pathways might be involved in this effect. NNC-55 induced the formation of autophagosomes but inhibited autophagy flux. Moreover, rapamycin, an autophagy activator, did not rescue myotube atrophy or apoptosis induced by NNC-55, and the autophagy inhibitors 3-MA and HCQ accelerated this damage. Further studies showed that the ERS inhibitors 4-PBA and TUDAC relieved NNC-55-induced damage and autophagy flux blockade. Finally, we found multisite muscle atrophy and decreased muscle function in Cacna1h-/- (TH-null) mice, as well as increased autophagy inhibition and apoptotic signals in the PFM of old WT mice after MVD and TH-null mice. Taken together, our results suggest that MVD-associated PFD is partially attributed to CACNA1H downregulation-induced PFM atrophy and that ERS is a potential therapeutic target for this disease.

| S-EPMC7181873 | biostudies-literature

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.

Project description:IntroductionEndoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle.MethodsHerein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4.ResultsIn C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects.DiscussionThus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.

| S-EPMC9816868 | biostudies-literature

Methods for monitoring endoplasmic reticulum stress and the unfolded protein response.

Project description:The endoplasmic reticulum (ER) is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the endoplasmic reticulum cause ER stress and activate a set of signaling pathways termed the Unfolded Protein Response (UPR). The UPR can promote cellular repair and sustained survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field. There are also many researchers not working directly on ER stress, but who wish to determine whether this response is activated in the system they are studying: thus, it is important to list a standard set of criteria for monitoring UPR in different model systems. Here, we discuss approaches that can be used by researchers to plan and interpret experiments aimed at evaluating whether the UPR and related processes are activated. We would like to emphasize that no individual assay is guaranteed to be the most appropriate one in every situation and strongly recommend the use of multiple assays to verify UPR activation.

| S-EPMC2821749 | biostudies-literature

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