scholarly journals Lipotoxicity in Kidney, Heart, and Skeletal Muscle Dysfunction

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1664 ◽  
Author(s):  
Hiroshi Nishi ◽  
Takaaki Higashihara ◽  
Reiko Inagi
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Lipid Synthesis ◽  
Fat Distribution ◽  
Unfolded Protein ◽  
Skeletal Muscle Dysfunction ◽  
Metabolic Imbalance ◽  
Extrarenal Complications ◽  
The Unfolded Protein Response ◽  
Protein Response

Dyslipidemia is a common nutritional and metabolic disorder in patients with chronic kidney disease. Accumulating evidence supports the hypothesis that prolonged metabolic imbalance of lipids leads to ectopic fat distribution in the peripheral organs (lipotoxicity), including the kidney, heart, and skeletal muscle, which accelerates peripheral inflammation and afflictions. Thus, lipotoxicity may partly explain progression of renal dysfunction and even extrarenal complications, including renal anemia, heart failure, and sarcopenia. Additionally, endoplasmic reticulum stress activated by the unfolded protein response pathway plays a pivotal role in lipotoxicity by modulating the expression of key enzymes in lipid synthesis and oxidation. Here, we review the molecular mechanisms underlying lipid deposition and resultant tissue damage in the kidney, heart, and skeletal muscle, with the goal of illuminating the nutritional aspects of these pathologies.

scholarly journals Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction

2021 ◽  
Vol 23 (1) ◽  
pp. 169
Author(s):  
Lisa A. Walter ◽  
Lauren P. Blake ◽  
Yann S. Gallot ◽  
Charles J. Arends ◽  
Randall S. Sozio ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sciatic Nerve ◽  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Sprague Dawley ◽  
Unfolded Protein ◽  
Potential Therapeutic Role ◽  
The Unfolded Protein Response ◽  
Protein Response

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

scholarly journals The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane.

1997 ◽  
Vol 8 (9) ◽  
pp. 1805-1814 ◽  
Author(s):  
J S Cox ◽  
R E Chapman ◽  
P Walter
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Lipid Synthesis ◽  
Secretory Proteins ◽  
Endoplasmic Reticulum Membrane ◽  
Yeast Saccharomyces Cerevisiae ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for production of both lumenal and membrane components of secretory pathway compartments. Secretory proteins are folded, processed, and sorted in the ER lumen and lipid synthesis occurs on the ER membrane itself. In the yeast Saccharomyces cerevisiae, synthesis of ER components is highly regulated: the ER-resident proteins by the unfolded protein response and membrane lipid synthesis by the inositol response. We demonstrate that these two responses are intimately linked, forming different branches of the same pathway. Furthermore, we present evidence indicating that this coordinate regulation plays a role in ER biogenesis.

scholarly journals RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions

2014 ◽  
Vol 5 (12) ◽  
pp. e1555-e1555 ◽  
Author(s):  
Y Estornes ◽  
M A Aguileta ◽  
C Dubuisson ◽  
J De Keyser ◽  
V Goossens ◽  
...  
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Life And Death ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and results in the activation of the unfolded protein response (UPR), which aims at restoring ER homeostasis. However, when the stress is too severe the UPR switches from being a pro-survival response to a pro-death one, and the molecular mechanisms underlying ER stress-mediated death have remained incompletely understood. In this study, we identified receptor interacting protein kinase 1 (RIPK1)—a kinase at the crossroad between life and death downstream of various receptors—as a new regulator of ER stress-induced death. We found that Ripk1-deficient MEFs are protected from apoptosis induced by ER stressors, which is reflected by reduced caspase activation and PARP processing. Interestingly, the pro-apoptotic role of Ripk1 is independent of its kinase activity, is not regulated by its cIAP1/2-mediated ubiquitylation, and does not rely on the direct regulation of JNK or CHOP, two reportedly main players in ER stress-induced death. Instead, we found that ER stress-induced apoptosis in these cells relies on death receptor-independent activation of caspase-8, and identified Ripk1 upstream of caspase-8. However, in contrast to RIPK1-dependent apoptosis downstream of TNFR1, we did not find Ripk1 associated with caspase-8 in a death-inducing complex upon unresolved ER stress. Our data rather suggest that RIPK1 indirectly regulates caspase-8 activation, in part via interaction with the ER stress sensor inositol-requiring protein 1 (IRE1).

scholarly journals The Role of the ER-Induced UPR Pathway and the Efficacy of Its Inhibitors and Inducers in the Inhibition of Tumor Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Anna Walczak ◽  
Kinga Gradzik ◽  
Jacek Kabzinski ◽  
Karolina Przybylowska-Sygut ◽  
Ireneusz Majsterek
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Unfolded Proteins ◽  
Cell Protection ◽  
Protection Mechanism ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Cancer is the second most frequent cause of death worldwide. It is considered to be one of the most dangerous diseases, and there is still no effective treatment for many types of cancer. Since cancerous cells have a high proliferation rate, it is pivotal for their proper functioning to have the well-functioning protein machinery. Correct protein processing and folding are crucial to maintain tumor homeostasis. Endoplasmic reticulum (ER) stress is one of the leading factors that cause disturbances in these processes. It is induced by impaired function of the ER and accumulation of unfolded proteins. Induction of ER stress affects many molecular pathways that cause the unfolded protein response (UPR). This is the way in which cells can adapt to the new conditions, but when ER stress cannot be resolved, the UPR induces cell death. The molecular mechanisms of this double-edged sword process are involved in the transition of the UPR either in a cell protection mechanism or in apoptosis. However, this process remains poorly understood but seems to be crucial in the treatment of many diseases that are related to ER stress. Hence, understanding the ER stress response, especially in the aspect of pathological consequences of UPR, has the potential to allow us to develop novel therapies and new diagnostic and prognostic markers for cancer.

scholarly journals Beyond the cell factory: Homeostatic regulation of and by the UPRER

2020 ◽  
Vol 6 (29) ◽  
pp. eabb9614
Author(s):  
Melissa G. Metcalf ◽  
Ryo Higuchi-Sanabria ◽  
Gilberto Garcia ◽  
C. Kimberly Tsui ◽  
Andrew Dillin
Keyword(s):  
Protein Misfolding ◽  
Lipid Synthesis ◽  
Transcriptional Response ◽  
Cell Factory ◽  
Unfolded Protein ◽  
Membrane Bound ◽  
Emerging Themes ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Cellular Components

The endoplasmic reticulum (ER) is commonly referred to as the factory of the cell, as it is responsible for a large amount of protein and lipid synthesis. As a membrane-bound organelle, the ER has a distinct environment that is ideal for its functions in synthesizing these primary cellular components. Many different quality control machineries exist to maintain ER stability under the stresses associated with synthesizing, folding, and modifying complex proteins and lipids. The best understood of these mechanisms is the unfolded protein response of the ER (UPRER), in which transmembrane proteins serve as sensors, which trigger a coordinated transcriptional response of genes dedicated for mitigating the stress. As the name suggests, the UPRER is most well described as a functional response to protein misfolding stress. Here, we focus on recent findings and emerging themes in additional roles of the UPRER outside of protein homeostasis, including lipid homeostasis, autophagy, apoptosis, and immunity.

Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle

2013 ◽  
Vol 304 (5) ◽  
pp. C422-C430 ◽  
Author(s):  
Michael F. O'Leary ◽  
Anna Vainshtein ◽  
Sobia Iqbal ◽  
Olga Ostojic ◽  
David A. Hood
Keyword(s):  
Molecular Mechanisms ◽  
Contractile Activity ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fraction ◽  
Adaptive Plasticity ◽  
Unfolded Protein ◽  
Muscle Disuse ◽  
Aging Muscle ◽  
The Unfolded Protein Response ◽  
Protein Response

Aging muscle exhibits a progressive decline in mass and strength, known as sarcopenia, and a decrease in the adaptive response to contractile activity. The molecular mechanisms mediating this reduced plasticity have yet to be elucidated. The purposes of this study were 1) to determine whether denervation-induced muscle disuse would increase the expression of autophagy genes and 2) to examine whether selective autophagy pathways (mitophagy) are altered in aged animals. Denervation reduced muscle mass in young and aged animals by 24 and 16%, respectively. Moreover, young animals showed a 50% decrease in mitochondrial content following denervation, an adaptation that was not matched by aged animals. Basal autophagy protein expression was higher in aged animals, whereas young animals exhibited a greater induction of autophagy proteins following denervation. Localization of LC3II, Parkin, and p62 was significantly increased in the mitochondrial fraction of young and aged animals following denervation. Moreover, the unfolded protein response marker CHOP and the mitochondrial dynamics protein Fis1 were increased by 17- and 2.5-fold, respectively, in aged animals. Lipofuscin granules within lysosomes were evident with aging and denervation. Thus reductions in the adaptive plasticity of aged muscle are associated with decreases in disuse-induced autophagy. These data indicate that the expression of autophagy proteins and their localization to mitochondria are not decreased in aged muscle; however, the induction of autophagy in response to disuse, along with downstream events such as lysosome function, is impaired. This may contribute to an accumulation of dysfunctional mitochondria in aged muscle.

scholarly journals GAS1Deficient Enhances UPR Activity inSaccharomyces cerevisiae

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Hong-jing Cui ◽  
Xin-gang Cui ◽  
Xia Jing ◽  
Yuan Yuan ◽  
Ya-qin Chen ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Yeast Cells ◽  
Unfolded Protein ◽  
Proliferation Ability ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Cycle Regulation ◽  
Wild Type Yeast

Beta-1,3-glucanosyltransferase (Gas1p) plays important roles in cell wall biosynthesis and morphogenesis and has been implicated in DNA damage responses and cell cycle regulation in fungi. Yeast Gas1p has also been reported to participate in endoplasmic reticulum (ER) stress responses. However, the precise roles and molecular mechanisms through which Gas1p affects these responses have yet to be elucidated. In this study, we constructedGAS1-deficient (gas1Δ) andGAS1-overexpressing (GAS1 OE) yeast strains and observed that thegas1Δstrain exhibited a decreased proliferation ability and a shorter replicative lifespan (RLS), as well as enhanced activity of the unfolded protein response (UPR) in the absence of stress. However, under the high-tunicamycin-concentration (an ER stress-inducing agent; 1.0 μg/mL) stress, thegas1Δyeast cells exhibited an increased proliferation ability compared with the wild-type yeast strain. In addition, our findings demonstrated thatIRE1andHAC1(two upstream modulators of the UPR) are required for the survival ofgas1Δyeast cells under the tunicamycin stress. On the other hand, we provided evidence that theGAS1overexpression caused an obvious sensitivity to the low-tunicamycin-concentration (0.25 μg/mL). Collectively, our results indicate that Gas1p plays an important role in the ageing and ER stress responses in yeast.

scholarly journals Stress macht Zellen resistent gegen Folsäure-basierte Chemotherapeutika

BIOspektrum ◽  
2020 ◽  
Vol 26 (6) ◽  
pp. 609-611
Author(s):  
Robert Ahrends ◽  
Jan Medenbach
Keyword(s):  
Gene Regulation ◽  
Stress Response ◽  
Molecular Mechanisms ◽  
Cellular Stress Response ◽  
Resistance To Therapy ◽  
Unfolded Protein ◽  
Stress Response Pathway ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The unfolded protein response (UPR), a cellular stress response pathway, is broadly implicated in disease and resistance to therapy. The molecular mechanisms that drive stress-mediated chemoresistance are, however, only poorly understood. We have employed a multiomics approach to determine UPR-induced gene regulation, revealing the UPR regulon. We further observe metabolic rewiring upon stress and resistance to Methotrexate, a widely-employed therapeutic reagent. The precise molecular characterization of the pathway driving resistance might lead to novel concepts in cancer therapy.

scholarly journals Cancer Microenvironment and Endoplasmic Reticulum Stress Response

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Claudia Giampietri ◽  
Simonetta Petrungaro ◽  
Silvia Conti ◽  
Antonio Facchiano ◽  
Antonio Filippini ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Molecular Mechanisms ◽  
Growth Promotion ◽  
Critical Role ◽  
Endoplasmic Reticulum Stress Response ◽  
Limiting Factors ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Different stressful conditions such as hypoxia, nutrient deprivation, pH changes, or reduced vascularization, potentially able to act as growth-limiting factors for tumor cells, activate the unfolded protein response (UPR). UPR is therefore involved in tumor growth and adaptation to severe environments and is generally cytoprotective in cancer. The present review describes the molecular mechanisms underlying UPR and able to promote survival and proliferation in cancer. The critical role of UPR activation in tumor growth promotion is discussed in detail for a few paradigmatic tumors such as prostate cancer and melanoma.

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