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Richter EA, Bilan PJ, Klip A. A comprehensive view of muscle glucose uptake: regulation by insulin, contractile activity, and exercise. Physiol Rev 2025; 105:1867-1945. [PMID: 40173020 DOI: 10.1152/physrev.00033.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/07/2024] [Accepted: 03/08/2025] [Indexed: 04/04/2025] Open
Abstract
Skeletal muscle is the main site of glucose deposition in the body during meals and the major glucose utilizer during physical activity. Although in both instances the supply of glucose from the circulation to the muscle is of paramount importance, in most conditions the rate-limiting step in glucose uptake, storage, and utilization is the transport of glucose across the muscle cell membrane. This step is dependent upon the translocation of the insulin- and contraction-responsive glucose transporter GLUT4 from intracellular storage sites to the sarcolemma and T tubules. Here, we first analyze how glucose can traverse the capillary wall into the muscle interstitial space. We then review the molecular processes that regulate GLUT4 translocation in response to insulin and muscle contractions and the methodologies utilized to unravel them. We further discuss how physical activity and inactivity, respectively, lead to increased and decreased insulin action in muscle and touch upon sex differences in glucose metabolism. Although many key processes regulating glucose uptake in muscle are known, the advent of newer and bioinformatics tools has revealed further molecular signaling processes reaching a staggering level of complexity. Much of this molecular mapping has emerged from cellular and animal studies and more recently from application of a variety of -omics in human tissues. In the future, it will be imperative to validate the translatability of results drawn from experimental systems to human physiology.
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Affiliation(s)
- Erik A Richter
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Philip J Bilan
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Amira Klip
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
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2
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Xiao T, Huang F, Guo Z, Cheng X, Duan J, Dai W, Yang B, Zhang Y, Tao L, Shen X. Black Raspberry Polyphenols Shape Metabolic Dysregulation and Perturbation in Gut Microbiota to Promote Lipid Metabolism and Liver Regeneration. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:7833-7856. [PMID: 40130403 DOI: 10.1021/acs.jafc.5c00702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Black raspberry as a functional food is a potential modulator of human metabolic disease. However, the role of black raspberry polyphenols (HSM) in shaping metabolic dysregulation and perturbation in gut microbiota (GM) to promote lipid metabolism and liver regeneration is unclear. In this work, the effects of HSM in mitigating metabolic disturbances and hepatic damage induced by a high-fat diet (HFD) and antibiotics (Abs) in mice were measured. HSM significantly alleviated HFD-induced obesity, insulin resistance, lipid and glucose metabolic dysregulation, as well as hepatic damage by activating the PI3K/AKT pathway and pregnane X receptor (PXR)-farnesoid X receptor (FXR) axis with improved GM, which was evidenced by short-chain fatty acids, 16S, and nontarget metabolism analysis. Excellent results were also evident in mice treated with Abs. Besides, HSM markedly inhibited key digestive enzymes associated with metabolic syndrome and also significantly enhanced antioxidant capacity after metabolized by GM. The discoveries underscored the potential of dietary HSM to manage lipid metabolism and liver regeneration within GM homeostasis.
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Affiliation(s)
- Ting Xiao
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The National Engineering Research Center of Miao's Medicines, Guizhou Yibai Pharmaceutical Co., Ltd., Guiyang 550008, China
| | - Feilong Huang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Zhenghong Guo
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
| | - Xingyan Cheng
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Jinchang Duan
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Weiyan Dai
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Bo Yang
- Department of Pharmacy, Zhejiang Academy of Traditional Chinese Medicine, Zhejiang Provincial Tongde Hospital, 234 Gucui Road, Hangzhou, Zhejiang 310013, China
| | - Yiquan Zhang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- Guizhou Hengba Pharmaceutical Co., Ltd., Jinyang Industry Knowledge Park, Guiyang National High-tech Industrial Development Zone, Guiyang 550008, China
| | - Ling Tao
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
| | - Xiangchun Shen
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmacology of Materia Medica (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
- The Department of Pharmaceutics of TCM (the High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, the Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, No. 6 Ankang Avenue, Guian New District, Guiyang, Guizhou 561113, China
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3
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Hansman DS, Du J, Casson RJ, Peet DJ. Eye on the horizon: The metabolic landscape of the RPE in aging and disease. Prog Retin Eye Res 2025; 104:101306. [PMID: 39433211 PMCID: PMC11833275 DOI: 10.1016/j.preteyeres.2024.101306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/23/2024]
Abstract
To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.
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Affiliation(s)
- David S Hansman
- School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
| | - Jianhai Du
- Department of Ophthalmology and Visual Sciences, Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USA
| | - Robert J Casson
- Discipline of Ophthalmology and Visual Science, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Daniel J Peet
- School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
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4
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Gallero S, Persson KW, Henríquez-Olguín C. Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species. FEBS Lett 2024; 598:2145-2159. [PMID: 38803005 DOI: 10.1002/1873-3468.14937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/10/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024]
Abstract
Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.
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Affiliation(s)
- Samantha Gallero
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
| | - Kaspar W Persson
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
| | - Carlos Henríquez-Olguín
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark
- Exercise Science Laboratory, Faculty of Medicine, Universidad Finis Terrae, Santiago, Chile
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5
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Othman MB, Takeda R, Sekita M, Okazaki K, Sakamoto K. Amber (Succinite) Extract Enhances Glucose Uptake through the Up-Regulation of ATP and Down-Regulation of ROS in Mouse C2C12 Cells. Pharmaceuticals (Basel) 2024; 17:586. [PMID: 38794156 PMCID: PMC11124190 DOI: 10.3390/ph17050586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Traditionally, amber (Succinite) has been used to alleviate all types of pain, skin allergies, and headaches. However, no studies have been conducted on its antidiabetic and antioxidant effects. In this study, differentiated skeletal muscle C2C12 cells were used to demonstrate the protective effects of amber (AMB) against H2O2-induced cell death. In addition, the effects of AMB on glucose uptake and ATP production were investigated. Our results showed that AMB at 10, 25, and 50 μg/mL suppressed the elevation of ROS production induced by H2O2 in a dose-dependent manner. Moreover, AMB enhanced glucose utilization in C2C12 cells through the improvement of ATP production and an increase in PGC-1α gene expression resulting in an amelioration of mitochondrial activity. On the other hand, AMB significantly increased the gene expression of glucose transporters GLUT4 and GLUT1. Our finding suggests that AMB can be used as a natural supplement for diabetes treatment and for the promotion of skeletal muscle function.
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Affiliation(s)
- Mahmoud Ben Othman
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan;
| | - Reiko Takeda
- Kohaku Bio Technology Co., Ltd., Morioka 020-8551, Japan; (R.T.); (M.S.); (K.O.)
| | - Marie Sekita
- Kohaku Bio Technology Co., Ltd., Morioka 020-8551, Japan; (R.T.); (M.S.); (K.O.)
| | - Kazuma Okazaki
- Kohaku Bio Technology Co., Ltd., Morioka 020-8551, Japan; (R.T.); (M.S.); (K.O.)
| | - Kazuichi Sakamoto
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan;
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6
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Veluthakal R, Esparza D, Hoolachan JM, Balakrishnan R, Ahn M, Oh E, Jayasena CS, Thurmond DC. Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression. Int J Mol Sci 2024; 25:1504. [PMID: 38338783 PMCID: PMC10855860 DOI: 10.3390/ijms25031504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 01/15/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.
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Affiliation(s)
- Rajakrishnan Veluthakal
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E. Duarte Rd, Duarte, CA 91010, USA; (D.E.); (J.M.H.); (R.B.); (M.A.); (E.O.); (C.S.J.)
| | | | | | | | | | | | | | - Debbie C. Thurmond
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E. Duarte Rd, Duarte, CA 91010, USA; (D.E.); (J.M.H.); (R.B.); (M.A.); (E.O.); (C.S.J.)
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White MR, Yates DT. Dousing the flame: reviewing the mechanisms of inflammatory programming during stress-induced intrauterine growth restriction and the potential for ω-3 polyunsaturated fatty acid intervention. Front Physiol 2023; 14:1250134. [PMID: 37727657 PMCID: PMC10505810 DOI: 10.3389/fphys.2023.1250134] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/14/2023] [Indexed: 09/21/2023] Open
Abstract
Intrauterine growth restriction (IUGR) arises when maternal stressors coincide with peak placental development, leading to placental insufficiency. When the expanding nutrient demands of the growing fetus subsequently exceed the capacity of the stunted placenta, fetal hypoxemia and hypoglycemia result. Poor fetal nutrient status stimulates greater release of inflammatory cytokines and catecholamines, which in turn lead to thrifty growth and metabolic programming that benefits fetal survival but is maladaptive after birth. Specifically, some IUGR fetal tissues develop enriched expression of inflammatory cytokine receptors and other signaling cascade components, which increases inflammatory sensitivity even when circulating inflammatory cytokines are no longer elevated after birth. Recent evidence indicates that greater inflammatory tone contributes to deficits in skeletal muscle growth and metabolism that are characteristic of IUGR offspring. These deficits underlie the metabolic dysfunction that markedly increases risk for metabolic diseases in IUGR-born individuals. The same programming mechanisms yield reduced metabolic efficiency, poor body composition, and inferior carcass quality in IUGR-born livestock. The ω-3 polyunsaturated fatty acids (PUFA) are diet-derived nutraceuticals with anti-inflammatory effects that have been used to improve conditions of chronic systemic inflammation, including intrauterine stress. In this review, we highlight the role of sustained systemic inflammation in the development of IUGR pathologies. We then discuss the potential for ω-3 PUFA supplementation to improve inflammation-mediated growth and metabolic deficits in IUGR offspring, along with potential barriers that must be considered when developing a supplementation strategy.
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Affiliation(s)
| | - Dustin T. Yates
- Stress Physiology Laboratory, Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, United States
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8
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Espinosa A, Casas M, Jaimovich E. Energy (and Reactive Oxygen Species Generation) Saving Distribution of Mitochondria for the Activation of ATP Production in Skeletal Muscle. Antioxidants (Basel) 2023; 12:1624. [PMID: 37627619 PMCID: PMC10451830 DOI: 10.3390/antiox12081624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/27/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Exercise produces oxidants from a variety of intracellular sources, including NADPH oxidases (NOX) and mitochondria. Exercise-derived reactive oxygen species (ROS) are beneficial, and the amount and location of these ROS is important to avoid muscle damage associated with oxidative stress. We discuss here some of the evidence that involves ROS production associated with skeletal muscle contraction and the potential oxidative stress associated with muscle contraction. We also discuss the potential role of H2O2 produced after NOX activation in the regulation of glucose transport in skeletal muscle. Finally, we propose a model based on evidence for the role of different populations of mitochondria in skeletal muscle in the regulation of ATP production upon exercise. The subsarcolemmal population of mitochondria has the enzymatic and metabolic components to establish a high mitochondrial membrane potential when fissioned at rest but lacks the capacity to produce ATP. Calcium entry into the mitochondria will further increase the metabolic input. Upon exercise, subsarcolemmal mitochondria will fuse to intermyofibrillar mitochondria and will transfer the mitochondria membrane potential to them. These mitochondria are rich in ATP synthase and will subsequentially produce the ATP needed for muscle contraction in long-term exercise. These events will optimize energy use and minimize mitochondria ROS production.
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Affiliation(s)
- Alejandra Espinosa
- Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8320000, Chile; (A.E.)
- San Felipe Campus, School of Medicine, Faculty of Medicine, Universidad de Valparaiso, San Felipe 2172972, Chile
| | - Mariana Casas
- Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8320000, Chile; (A.E.)
| | - Enrique Jaimovich
- Center for Studies of Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8320000, Chile; (A.E.)
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9
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Kakehi S, Tamura Y, Ikeda SI, Kaga N, Taka H, Nishida Y, Kawamori R, Watada H. Physical inactivity induces insulin resistance in plantaris muscle through protein tyrosine phosphatase 1B activation in mice. Front Physiol 2023; 14:1198390. [PMID: 37389126 PMCID: PMC10300557 DOI: 10.3389/fphys.2023.1198390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 06/05/2023] [Indexed: 07/01/2023] Open
Abstract
Inactivity causes insulin resistance in skeletal muscle and exacerbates various lifestyle-related diseases. We previously found that 24-h hindlimb cast immobilization (HCI) of the predominantly slow-twitch soleus muscle increased intramyocellular diacylglycerol (IMDG) and insulin resistance by activation of lipin1, and HCI after a high-fat diet (HFD) further aggravated insulin resistance. Here, we investigated the effects of HCI on the fast-twitch-predominant plantaris muscle. HCI reduced the insulin sensitivity of plantaris muscle by approximately 30%, and HCI following HFD dramatically reduced insulin sensitivity by approximately 70% without significant changes in the amount of IMDG. Insulin-stimulated phosphorylation levels of insulin receptor (IR), IR substrate-1, and Akt were reduced in parallel with the decrease in insulin sensitivity. Furthermore, tyrosine phosphatase 1B (PTP1B), a protein known to inhibit insulin action by dephosphorylating IR, was activated, and PTP1B inhibition canceled HCI-induced insulin resistance. In conclusion, HCI causes insulin resistance in the fast-twitch-predominant plantaris muscle as well as in the slow-twitch-predominant soleus muscle, and HFD potentiates these effects in both muscle types. However, the mechanism differed between soleus and plantaris muscles, since insulin resistance was mediated by the PTP1B inhibition at IR in plantaris muscle.
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Affiliation(s)
- Saori Kakehi
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Shin-ichi Ikeda
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Naoko Kaga
- Division of Proteomics and Biomolecular Science, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hikari Taka
- Division of Proteomics and Biomolecular Science, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuya Nishida
- Department of Metabolism and Endocrinology, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Tokyo, Japan
- Sportology Center, Tokyo, Japan
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10
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Bungau AF, Radu AF, Bungau SG, Vesa CM, Tit DM, Endres LM. Oxidative stress and metabolic syndrome in acne vulgaris: Pathogenetic connections and potential role of dietary supplements and phytochemicals. Biomed Pharmacother 2023; 164:115003. [PMID: 37315434 DOI: 10.1016/j.biopha.2023.115003] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/06/2023] [Accepted: 06/08/2023] [Indexed: 06/16/2023] Open
Abstract
Acne vulgaris is a highly prevalent skin condition caused by androgen-induced elevated sebum secretion, abnormal keratinization, bacterial colonization, and inflammation. Current research indicates a link between acne vulgaris and the metabolic syndrome, a group of disorders that includes obesity, insulin resistance, hypertension, and dyslipidemia. This link is thought to be modulated by excessive concentrations of oxidative stress markers and chronic inflammation, which are included in the pathophysiological mechanisms shared by both conditions. Excessive generation of reactive oxygen species damages cellular components and initiates an inflammatory response, hence promoting the development of both disorders. The current narrative review focuses on the molecular implications of inflammatory, hormonal, and environmental factors in the acne-metabolic syndrome correlation. Furthermore, it outlines the current state of knowledge related to the phyto-therapeutic approach to these conditions as an adjuvant strategy to allopathic treatment, but future multicenter and larger-scale research studies are needed establish new algorithms to be included in the future management of patients with these conditions.
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Affiliation(s)
- Alexa Florina Bungau
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Andrei Flavius Radu
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania.
| | - Simona Gabriela Bungau
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania.
| | - Cosmin Mihai Vesa
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Delia Mirela Tit
- Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Laura Maria Endres
- Department of Psycho-Neurosciences and Recovery, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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11
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Fernández-Puente E, Martín-Prieto E, Márquez CM, Palomero J. Effect of RONS-Induced Intracellular Redox Homeostasis in 6-NBDG/Glucose Uptake in C2C12 Myotubes and Single Isolated Skeletal Muscle Fibres. Int J Mol Sci 2023; 24:ijms24098082. [PMID: 37175789 PMCID: PMC10179233 DOI: 10.3390/ijms24098082] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
The glucose uptake in skeletal muscle is essential to produce energy through ATP, which is needed by this organ to maintain vital functions. The impairment of glucose uptake compromises the metabolism and function of skeletal muscle and other organs and is a feature of diabetes, obesity, and ageing. There is a need for research to uncover the mechanisms involved in the impairment of glucose uptake in skeletal muscle. In this study, we adapted, developed, optimised, and validated a methodology based on the fluorescence glucose analogue 6-NBDG, combined with a quantitative fluorescence microscopy image analysis, to determine the glucose uptake in two models of skeletal muscle cells: C2C12 myotubes and single fibres isolated from muscle. It was proposed that reactive oxygen and nitrogen species (RONS) and redox homeostasis play an important role in the modulation of intracellular redox signalling pathways associated with glucose uptake. In this study, we prove that the prooxidative intracellular redox environment under oxidative eustress produced by RONS such as hydrogen peroxide and nitric oxide improves glucose uptake in skeletal muscle cells. However, when oxidation is excessive, oxidative distress occurs, and cellular viability is compromised, although there might be an increase in the glucose uptake. Based on the results of this study, the determination of 6-NBDG/glucose uptake in myotubes and skeletal muscle cells is feasible, validated, and will contribute to improve future research.
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Affiliation(s)
- Escarlata Fernández-Puente
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
- Institute of Neurosciences of Castilla y León (INCyL), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Eva Martín-Prieto
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
- Institute of Neurosciences of Castilla y León (INCyL), 37007 Salamanca, Spain
| | - Carlos Manuel Márquez
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
| | - Jesús Palomero
- Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain
- Institute of Neurosciences of Castilla y León (INCyL), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
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12
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Argaev-Frenkel L, Rosenzweig T. Redox Balance in Type 2 Diabetes: Therapeutic Potential and the Challenge of Antioxidant-Based Therapy. Antioxidants (Basel) 2023; 12:antiox12050994. [PMID: 37237860 DOI: 10.3390/antiox12050994] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/19/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Oxidative stress is an important factor in the development of type 2 diabetes (T2D) and associated complications. Unfortunately, most clinical studies have failed to provide sufficient evidence regarding the benefits of antioxidants (AOXs) in treating this disease. Based on the known complexity of reactive oxygen species (ROS) functions in both the physiology and pathophysiology of glucose homeostasis, it is suggested that inappropriate dosing leads to the failure of AOXs in T2D treatment. To support this hypothesis, the role of oxidative stress in the pathophysiology of T2D is described, together with a summary of the evidence for the failure of AOXs in the management of diabetes. A comparison of preclinical and clinical studies indicates that suboptimal dosing of AOXs might explain the lack of benefits of AOXs. Conversely, the possibility that glycemic control might be adversely affected by excess AOXs is also considered, based on the role of ROS in insulin signaling. We suggest that AOX therapy should be given in a personalized manner according to the need, which is the presence and severity of oxidative stress. With the development of gold-standard biomarkers for oxidative stress, optimization of AOX therapy may be achieved to maximize the therapeutic potential of these agents.
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Affiliation(s)
| | - Tovit Rosenzweig
- Department of Molecular Biology, Ariel University, Ariel 4070000, Israel
- Adison School of Medicine, Ariel University, Ariel 4070000, Israel
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13
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Li X, Chang E, Cui J, Zhao H, Hu C, O’Dea KP, Tirlapur N, Balboni G, Zhang J, Ying L, Ma D. Bv8 mediates myeloid cell migration and enhances malignancy of colorectal cancer. Front Immunol 2023; 14:1158045. [PMID: 37090721 PMCID: PMC10113555 DOI: 10.3389/fimmu.2023.1158045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/27/2023] [Indexed: 04/09/2023] Open
Abstract
Colorectal cancer (CRC) is the third most predominant malignancy in the world. Although the importance of immune system in cancer development has been well established, the underlying mechanisms remain to be investigated further. Here we studied a novel protein prokineticin 2 (Prok2, also known as Bv8) as a key pro-tumoral factor in CRC progression in in vitro and ex vivo settings. Human colorectal tumor tissues, myeloid cell lines (U937 cells and HL60 cells) and colorectal cancer cell line (Caco-2 cells) were used for various studies. Myeloid cell infiltration (especially neutrophils) and Bv8 accumulation were detected in human colorectal tumor tissue with immunostaining. The chemotactic effects of Bv8 on myeloid cells were presented in the transwell assay and chemotaxis assy. Cultured CRC cells treated with myeloid cells or Bv8 produced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF). Furthermore, ROS and VEGF acted as pro-angiogenesis buffer in myeloid cell-infiltrated CRC microenvironment. Moreover, myeloid cells or Bv8 enhanced energy consumption of glycolysis ATP and mitochondria ATP of CRC cells. Interestingly, myeloid cells increased CRC cell viability, but CRC cells decreased the viability of myeloid cells. ERK signalling pathway in CRC cells was activated in the presence of Bv8 or co-cultured myeloid cells. In conclusion, our data indicated the vital roles of Bv8 in myeloid cell infiltration and CRC development, suggesting that Bv8 may be a potential therapeutic target for colorectal cancer-related immunotherapy.
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Affiliation(s)
- Xiaomeng Li
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Enqiang Chang
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
- Department of Anaesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiang Cui
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Hailin Zhao
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Cong Hu
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Kieran P. O’Dea
- Division of Translational Critical Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Nikhil Tirlapur
- Division of Translational Critical Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Gianfranco Balboni
- Department of Life and Environmental Sciences, University of Cagliari, Monserrato, Italy
| | - Jiaqiang Zhang
- Department of Anaesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Jiaqiang Zhang, ; Liming Ying, ; Daqing Ma,
| | - Liming Ying
- National Heart and Lung Institute, Imperial College London, Molecular Sciences Research Hub, London, United Kingdom
- *Correspondence: Jiaqiang Zhang, ; Liming Ying, ; Daqing Ma,
| | - Daqing Ma
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
- *Correspondence: Jiaqiang Zhang, ; Liming Ying, ; Daqing Ma,
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14
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Torres SM, Carmo FP, Monteiro LC, Silva C, Andrade N, Martel F. Gallic acid markedly stimulates GLUT1-mediated glucose uptake by the AsPC-1 pancreatic cancer cell line. Can J Physiol Pharmacol 2023; 101:90-105. [PMID: 36688470 DOI: 10.1139/cjpp-2022-0260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Phenolic acids are recognized as chemopreventive and chemotherapeutic agents. Altered glucose and glutamine metabolism are recognized hallmarks of cancer cells. We aimed to test the influence of phenolic acids on glucose and glutamine cellular uptake by a breast (MCF-7) and a pancreatic (AsPC-1) cancer cell line. Several phenolic acids (caffeic, ferrulic, proctocatechuic, coumaric and gallic acid) affected 3H-glutamine and/or 3H-deoxy-d-glucose (3H-DG) uptake. Gallic acid (100 µM) caused a 3-fold increase in 3H-DG uptake by AsPC-1 cells, associated with a 3.7-fold increase in lactic acid production. Gallic acid stimulated GLUT1-mediated 3H-DG uptake and increased the affinity of this transporter for 3H-DG. We further verified that gallic acid does not change GLUT1 transcription rates and cellular redox state and that its effect does not involve PI3K, mTOR and MAP kinases and is not associated with a proproliferative effect. Gallic acid also increased 3H-DG uptake by MCF-7 cells, although less potently. Further investigation is necessary to elucidate the cellular pathways involved in this effect of gallic acid.
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Affiliation(s)
| | - Francisca P Carmo
- Faculty of Sciences, University of Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Luís C Monteiro
- Faculty of Sciences, University of Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Cláudia Silva
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
| | - Nelson Andrade
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,REQUIMTE/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Fátima Martel
- Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
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15
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Li Y, Lin S, Xu X, Jin W, Su Y, Yuan F, Zhang Y, Li Z, Zhou Y, Zhu L, Zhang L. Skeletal muscle HSF1 prevents insulin resistance by improving glucose utilization. FASEB J 2022; 36:e22667. [PMID: 36421020 DOI: 10.1096/fj.202201160rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 11/27/2022]
Abstract
The regulation of muscle glucose utilization has significant potential for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Heat shock factor 1 (HSF1) is involved in cellular metabolism and regulation of muscle metabolism. However, it is unclear how HSF1 regulates muscle glucose metabolism. In the present study, the development of obesity in mice was associated with HSF1 downregulation. Serum samples and muscle biopsies were obtained from obese and healthy humans. Fasting glucose and insulin levels and the homeostasis model assessment of insulin resistance value showed that obesity was associated with insulin resistance. The skeletal muscle level of HSF1 was decreased in obese and ob/ob mice. HSF1 was selectively over-expressed in the skeletal muscles of high fat diet (HFD)-fed mice. Muscle HSF1 over-expression successfully triggered glycolytic-to-oxidative myofiber switch and increased fatty acid metabolism and insulin sensitivity in the skeletal muscles of HFD-fed mice. Moreover, HSF1 improved energy expenditure and blocked muscle accumulation of triglycerides in HFD-fed mice. Consequently, muscle HSF1 mitigated the impaired muscle insulin signaling and insulin resistance in HFD-fed mice. In conclusion, T2DM and obesity in HFD-fed mice may be treated with selective HSF1-directed programming of exercise-like effects in skeletal muscle. These findings may aid the development of a new therapeutic approach for obesity and T2DM.
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Affiliation(s)
- Yun Li
- Department of Pediatric Laboratory, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Shibo Lin
- Department of Bariatric and Metabolic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xu Xu
- Department of Pediatrics, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Weilai Jin
- Department of Pediatric Laboratory, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Yinglin Su
- Department of Neonatology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Fuqiang Yuan
- Department of Pediatric Laboratory, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Yiting Zhang
- Department of Pediatric Laboratory, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Zhengying Li
- Department of Neonatology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Yahui Zhou
- Department of Neonatology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Lihong Zhu
- Department of Pediatrics, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
| | - Le Zhang
- Department of Neonatology, The Affiliated Wuxi Children's Hospital of Nanjing Medical University, Wuxi, China
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16
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Redox Control of Signalling Responses to Contractile Activity and Ageing in Skeletal Muscle. Cells 2022; 11:cells11101698. [PMID: 35626735 PMCID: PMC9139227 DOI: 10.3390/cells11101698] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 02/06/2023] Open
Abstract
Research over almost 40 years has established that reactive oxygen species are generated at different sites in skeletal muscle and that the generation of these species is increased by various forms of exercise. Initially, this was thought to be potentially deleterious to skeletal muscle and other tissues, but more recent data have identified key roles of these species in muscle adaptations to exercise. The aim of this review is to summarise our current understanding of these redox signalling roles of reactive oxygen species in mediating responses of muscle to contractile activity, with a particular focus on the effects of ageing on these processes. In addition, we provide evidence that disruption of the redox status of muscle mitochondria resulting from age-associated denervation of muscle fibres may be an important factor leading to an attenuation of some muscle responses to contractile activity, and we speculate on potential mechanisms involved.
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17
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Argaev-Frenkel L, Rosenzweig T. Complexity of NAC Action as an Antidiabetic Agent: Opposing Effects of Oxidative and Reductive Stress on Insulin Secretion and Insulin Signaling. Int J Mol Sci 2022; 23:ijms23062965. [PMID: 35328386 PMCID: PMC8950759 DOI: 10.3390/ijms23062965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 02/05/2023] Open
Abstract
Dysregulated redox balance is involved in the pathogenesis of type 2 diabetes. While the benefit of antioxidants in neutralizing oxidative stress is well characterized, the potential harm of antioxidant-induced reductive stress is unclear. The aim of this study was to investigate the dose-dependent effects of the antioxidant N-acetylcysteine (NAC) on various tissues involved in the regulation of blood glucose and the mechanisms underlying its functions. H2O2 was used as an oxidizing agent in order to compare the outcomes of oxidative and reductive stress on cellular function. Cellular death in pancreatic islets and diminished insulin secretion were facilitated by H2O2-induced oxidative stress but not by NAC. On the other hand, myotubes and adipocytes were negatively affected by NAC-induced reductive stress, as demonstrated by the impaired transmission of insulin signaling and glucose transport, as opposed to H2O2-stimulatory action. This was accompanied by redox balance alteration and thiol modifications of proteins. The NAC-induced deterioration of insulin signaling was also observed in healthy mice, while both insulin secretion and insulin signaling were improved in diabetic mice. This study establishes the tissue-specific effects of NAC and the importance of the delicate maintenance of redox balance, emphasizing the challenge of implementing antioxidant therapy in the clinic.
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Affiliation(s)
| | - Tovit Rosenzweig
- Department of Molecular Biology, Ariel University, Ariel 4070000, Israel;
- Department of Nutritional Studies, Ariel University, Ariel 4070000, Israel
- Correspondence: ; Tel.: +972-3937-1433
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18
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Redox Regulation and Oxidative Stress in Mammalian Oocytes and Embryos Developed In Vivo and In Vitro. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182111374. [PMID: 34769890 PMCID: PMC8583213 DOI: 10.3390/ijerph182111374] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/25/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022]
Abstract
Oocytes and preimplantation embryos require careful regulation of the redox environment for optimal development both in vivo and in vitro. Reactive oxygen species (ROS) are generated throughout development as a result of cellular metabolism and enzyme reactions. ROS production can result in (i) oxidative eustress, where ROS are helpful signalling molecules with beneficial physiological functions and where the redox state of the cell is maintained within homeostatic range by a closely coupled system of antioxidants and antioxidant enzymes, or (ii) oxidative distress, where excess ROS are deleterious and impair normal cellular function. in vitro culture of embryos exacerbates ROS production due to a range of issues including culture-medium composition and laboratory culture conditions. This increase in ROS can be detrimental not only to assisted reproductive success rates but can also result in epigenetic and genetic changes in the embryo, resulting in transgenerational effects. This review examines the effects of oxidative stress in the oocyte and preimplantation embryo in both the in vivo and in vitro environment, identifies mechanisms responsible for oxidative stress in the oocyte/embryo in culture and approaches to reduce these problems, and briefly examines the potential impacts on future generations.
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19
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Zhu Y, Jing L, Li X, Zheng D, Zhou G, Zhang Y, Sang Y, Shi Z, Sun Z, Zhou X. Decabromodiphenyl ether disturbs hepatic glycolipid metabolism by regulating the PI3K/AKT/GLUT4 and mTOR/PPARγ/RXRα pathway in mice and L02 cells. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 763:142936. [PMID: 33138992 DOI: 10.1016/j.scitotenv.2020.142936] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 09/25/2020] [Accepted: 10/05/2020] [Indexed: 06/11/2023]
Abstract
Decabromodiphenyl ether (BDE-209) is a persistent environmental pollutant that poses great risks to human health and has been associated with glucose and lipid metabolism. However, the mechanisms by which BDE-209 disturbs glycolipid metabolism in the liver remain unclear. Therefore, this study sought to confirm the effects of BDE-209 on glycolipid metabolism in mice livers and L02 cells to elucidate potential mechanisms of action. In vivo BDE-209 exposure caused histological damage and lipid accumulation, elevated glucose, low-density lipoprotein, total cholesterol, and triglyceride levels, and decreased glycogen and high-density lipoprotein levels in mice livers. Moreover, in vitro BDE-209 exposure not only induced L02 cells cytotoxicity (i.e., reduced cell viability and increased LDH leakage and ROS generation) but also increased glucose and triglyceride concentrations in L02 cells. Furthermore, IGF-1, an activator of the PI3K-AKT pathway, markedly inhibited BDE-209-induced glucose concentration increase in L02 cells and antagonized the inhibitory effect of BDE-209 on the PI3K/AKT/GLUT4 pathway by counteracting the changes in the expression levels of p-IRS, AKT, PI3K, p-AKT, and GLUT4. Moreover, GW9662, a PPARγ inhibitor, blocked lipid accumulation and the upregulation of the mTOR/PPARγ/RXRα pathway in L02 cells induced by BDE-209 by relieving the increases in p-mTOR, PPARγ, and RXRα protein expression levels. In summary, this study revealed that BDE-209 disrupted glycolipid metabolism by inhibiting the PI3K/AKT/GLUT4 pathway and activating the mTOR/PPARγ/RXRα pathway.
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Affiliation(s)
- Yupeng Zhu
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China; Haidian Maternal&Child Health Hospital, Health Care Department for Women, Beijing 100080, China
| | - Li Jing
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Xiangyang Li
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Dan Zheng
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Guiqing Zhou
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Yue Zhang
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Yujian Sang
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Zhixiong Shi
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Zhiwei Sun
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Xianqing Zhou
- Department of Toxicology and Hygienic Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
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20
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Bouviere J, Fortunato RS, Dupuy C, Werneck-de-Castro JP, Carvalho DP, Louzada RA. Exercise-Stimulated ROS Sensitive Signaling Pathways in Skeletal Muscle. Antioxidants (Basel) 2021; 10:antiox10040537. [PMID: 33808211 PMCID: PMC8066165 DOI: 10.3390/antiox10040537] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/16/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Physical exercise represents a major challenge to whole-body homeostasis, provoking acute and adaptative responses at the cellular and systemic levels. Different sources of reactive oxygen species (ROS) have been described in skeletal muscle (e.g., NADPH oxidases, xanthine oxidase, and mitochondria) and are closely related to the physiological changes induced by physical exercise through the modulation of several signaling pathways. Many signaling pathways that are regulated by exercise-induced ROS generation, such as adenosine monophosphate-activated protein kinase (AMPK), mitogen activated protein kinase (MAPK), nuclear respiratory factor2 (NRF2), and PGC-1α are involved in skeletal muscle responses to physical exercise, such as increased glucose uptake, mitochondriogenesis, and hypertrophy, among others. Most of these adaptations are blunted by antioxidants, revealing the crucial role played by ROS during and after physical exercise. When ROS generation is either insufficient or exacerbated, ROS-mediated signaling is disrupted, as well as physical exercise adaptations. Thus, an understanding the limit between "ROS that can promote beneficial effects" and "ROS that can promote harmful effects" is a challenging question in exercise biology. The identification of new mediators that cause reductive stress and thereby disrupt exercise-stimulated ROS signaling is a trending on this topic and are covered in this current review.
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Affiliation(s)
- Jessica Bouviere
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Rodrigo S. Fortunato
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Corinne Dupuy
- Université Paris-Saclay, UMR 9019CNRS, Gustave Roussy, 94800 Villejuif, France;
| | - Joao Pedro Werneck-de-Castro
- Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Denise P. Carvalho
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
| | - Ruy A. Louzada
- Institut of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (J.B.); (R.S.F.); (D.P.C.)
- Université Paris-Saclay, UMR 9019CNRS, Gustave Roussy, 94800 Villejuif, France;
- Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- Correspondence:
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21
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Luo Z, Fu C, Li T, Gao Q, Miao D, Xu J, Zhao Y. Hypoglycemic Effects of Licochalcone A on the Streptozotocin-Induced Diabetic Mice and Its Mechanism Study. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:2444-2456. [PMID: 33605141 DOI: 10.1021/acs.jafc.0c07630] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a type of metabolic illness based on relatively insufficient insulin secretion and insulin resistance (IR) as pathophysiological bases. Currently, it is the main type of diabetes. Hypoglycemic and hypolipidemic effects of licochalcone A (LicA) on high-fat diet and streptozocin-caused T2DM were studied. LicA can remarkably decline the IR index and blood glucose and serum lipid levels. Also, the treatment of LicA can improve the "three more and one less" phenomenon in T2DM mice, such as excessive drinking, eating, urine, and weight loss. In addition, LicA can improve oral glucose tolerance, pancreatic injury, and liver enlargement in T2DM mice. Network pharmacology analysis demonstrated that the observed pharmacological effects were mediated by regulating the insulin signal transduction pathway. Therefore, the PI3K/Akt-signaling pathway was selected for verification; it was demonstrated that LicA could improve the insulin-signaling pathway, protect islet cells, improve IR, reduce blood glucose levels, and alleviate lipid metabolism disorder. Its mechanism of influence may be closely related to LicA up-regulating the liver and pancreas IRS-2/PI3K/AKT-signaling pathway. Among them, the high-dose group of LicA had the best effect, which provided an idea for the use of LicA as a nutritional agent in the cure of T2DM.
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Affiliation(s)
- Zhonghua Luo
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Chaofan Fu
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Tao Li
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Qingqing Gao
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Dongyu Miao
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jing Xu
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yuqing Zhao
- Shenyang Pharmaceutical University, Shenyang 110016, China
- Key Laboratory of Structure-based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
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Anti-diabetic effects of sea cucumber (Holothuria nobilis) hydrolysates in streptozotocin and high-fat-diet induced diabetic rats via activating the PI3K/Akt pathway. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104224] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Wu SJ, Tung YJ, Ng LT. Anti-diabetic effects of Grifola frondosa bioactive compound and its related molecular signaling pathways in palmitate-induced C2C12 cells. JOURNAL OF ETHNOPHARMACOLOGY 2020; 260:112962. [PMID: 32422357 DOI: 10.1016/j.jep.2020.112962] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/16/2020] [Accepted: 05/07/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Grifola frondosa (GF), a high value medicinal mushroom, is popularly consumed as traditional medicines and health foods in China and Japan. It is a herbal medicine traditionally used for treating inflammation, cancer and diabetes. AIM OF THE STUDY This study aimed to examine the anti-diabetic effects of a GF bioactive compound ergosterol peroxide (EPO), and its mechanism(s) of action in palmitate (PA)-induced C2C12 cells. MATERIALS AND METHODS EPO was isolated and purified from GF fruiting bodies, and used to test for anti-diabetic activity in PA-induced murine C2C12 skeletal muscle cells through measuring glucose uptake, intracellular ROS production, and expressions of MAPKs, IRS-1, PI3K, Akt and GLUT-4 proteins. RESULTS EPO significantly up-regulated glucose absorption and increased cell growth. At 5 μM, EPO significantly enhanced glucose uptake and decreased ROS formation, as well as up-regulated the expression of IRS-1, p-IRS-1, PI3K, Akt, p-Akt, and GLUT-4 proteins in PA-induced cells, while their p-JNK and p-p38 expression were down-regulated. GLUT-4 siRNA treatment effectively down-regulated the EPO-induced absorption of glucose and inhibited the expression of GLUT-4. CONCLUSION These results suggest that the anti-diabetic effect of GF was from its bioactive compound EPO through the inhibition of ROS production, up-regulation of glucose absorption, and modulation of PI3K/Akt, MAPKs and GLUT-4 signaling transduction pathways.
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Affiliation(s)
- Shu-Jing Wu
- Department of Nutritional Health, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Yi-Jou Tung
- Department of Nutritional Health, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Lean-Teik Ng
- Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan.
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Margaritelis NV, Paschalis V, Theodorou AA, Kyparos A, Nikolaidis MG. Redox basis of exercise physiology. Redox Biol 2020; 35:101499. [PMID: 32192916 PMCID: PMC7284946 DOI: 10.1016/j.redox.2020.101499] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/20/2020] [Accepted: 03/05/2020] [Indexed: 12/15/2022] Open
Abstract
Redox reactions control fundamental processes of human biology. Therefore, it is safe to assume that the responses and adaptations to exercise are, at least in part, mediated by redox reactions. In this review, we are trying to show that redox reactions are the basis of exercise physiology by outlining the redox signaling pathways that regulate four characteristic acute exercise-induced responses (muscle contractile function, glucose uptake, blood flow and bioenergetics) and four chronic exercise-induced adaptations (mitochondrial biogenesis, muscle hypertrophy, angiogenesis and redox homeostasis). Based on our analysis, we argue that redox regulation should be acknowledged as central to exercise physiology.
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Affiliation(s)
- N V Margaritelis
- Department of Physical Education and Sport Science at Serres, Aristotle University of Thessaloniki, Thessaloniki, Greece; Dialysis Unit, 424 General Military Hospital of Thessaloniki, Thessaloniki, Greece.
| | - V Paschalis
- School of Physical Education and Sport Science, National and Kapodistrian University of Athens, Athens, Greece
| | - A A Theodorou
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
| | - A Kyparos
- Department of Physical Education and Sport Science at Serres, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - M G Nikolaidis
- Department of Physical Education and Sport Science at Serres, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Iaccarino G, Franco D, Sorriento D, Strisciuglio T, Barbato E, Morisco C. Modulation of Insulin Sensitivity by Exercise Training: Implications for Cardiovascular Prevention. J Cardiovasc Transl Res 2020; 14:256-270. [PMID: 32737757 PMCID: PMC8043859 DOI: 10.1007/s12265-020-10057-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/28/2020] [Indexed: 12/11/2022]
Abstract
The beneficial effects of physical activity on the cardiovascular system nowadays have achieved the relevance of clinical evidence. In fact, several studies have documented the benefits of exercise training in the prevention of the cardiovascular risk. Abnormalities of insulin signaling transduction account for the impairment of insulin sensitivity and development of insulin resistance, which, in turn, is responsible for the enhancement of cardiovascular risk. Insulin sensitivity is related to the degree of physical activity, and physical training has been shown to ameliorate insulin action in insulin-resistant subjects. This effect is mediated by the improvement of the molecular abnormalities that are responsible of the insulin resistance, contributing in this way to restore the physiological insulin sensitivity. However, it should be underlined that mechanisms that account for this phenomenon are extremely complex and still unclear. Further studies are required to better clarify the molecular basis of the exercise-evoked improvement of insulin signal.
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