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Guo Z, Li J, Hu J, An G, Wang C. Deciphering the joint intracellular and extracellular regulatory strategies of toxigenic Microcystis to achieve intraspecific competitive advantage: An integrated multi-omics analysis with novel allelochemicals identified. WATER RESEARCH 2025; 283:123774. [PMID: 40398052 DOI: 10.1016/j.watres.2025.123774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/10/2025] [Accepted: 05/02/2025] [Indexed: 05/23/2025]
Abstract
Global increase in Microcystis-dominated cyanobacterial blooms (MCBs) severely threatens ecological and human health. Intraspecific interaction between microcystin (MC)-producing (MC+) Microcystis and co-existing MC-free (MC-) Microcystis influences the relative abundance of MC+Microcystis, ultimately determining the toxicity and hazard of MCBs. However, specific allelochemicals driving this interaction and underlying molecular mechanisms remain unclear. This study confirmed that intraspecific interaction promoted the competitive advantage of MC+Microcystis over MC-Microcystis and unveiled the joint intracellular and extracellular regulatory strategies of MC+Microcystis based on proteomics-metabolomics analyses and biochemical validation. Intracellularly, MC+Microcystis enhanced pentose phosphate pathway and lipid and fatty acid biosynthesis to maintain cellular functions and membrane stability, but inhibited glycolysis, tricarboxylic acid cycle, and protein biosynthesis to optimize energy utilization for growth and proliferation. Extracellularly, MC+Microcystis released allelochemicals, including cytidine diphosphate-diacylglycerol and N-acyl-homoserine lactones, to inhibit MC-Microcystis growth by 13.53% and 16.39%, respectively, thereby achieving its competitive advantage. In contrast, MC-Microcystis exhibited the suppressed photosynthesis and oxidative phosphorylation, imbalanced anti-inflammatory responses, nucleic acid degradation, and membrane damage, resulting in its competitive disadvantage in co-culture. These findings provide new insights into the competitive dynamics between MC+ and MC-Microcystis, and their involved implications for aquatic ecosystem health.
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Affiliation(s)
- Zhonghui Guo
- College of Resources and Environmental Sciences, China Agricultural University, Beijing 100193, China; Beijing Key Laboratory of Biodiversity and Organic Farming, China Agricultural University, Beijing 100193, China
| | - Jieming Li
- College of Resources and Environmental Sciences, China Agricultural University, Beijing 100193, China; Beijing Key Laboratory of Biodiversity and Organic Farming, China Agricultural University, Beijing 100193, China.
| | - Jiaqi Hu
- College of Resources and Environmental Sciences, China Agricultural University, Beijing 100193, China; Beijing Key Laboratory of Biodiversity and Organic Farming, China Agricultural University, Beijing 100193, China
| | - Guangqi An
- College of Resources and Environmental Sciences, China Agricultural University, Beijing 100193, China; Beijing Key Laboratory of Biodiversity and Organic Farming, China Agricultural University, Beijing 100193, China
| | - Chengyu Wang
- College of Resources and Environmental Sciences, China Agricultural University, Beijing 100193, China; Beijing Key Laboratory of Biodiversity and Organic Farming, China Agricultural University, Beijing 100193, China
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Kalenta H, Kilroe SP, Romsdahl TB, Marchant ED, Maroto R, Linares JJ, Russell WK, Rasmussen BB. Constitutively active mTORC1 signaling modifies the skeletal muscle metabolome and lipidome response to exercise. J Appl Physiol (1985) 2025; 138:1173-1186. [PMID: 40215109 DOI: 10.1152/japplphysiol.00987.2024] [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: 12/17/2024] [Revised: 01/21/2025] [Accepted: 04/04/2025] [Indexed: 05/01/2025] Open
Abstract
A chronic increase in the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling is implicated in reduced longevity, altered metabolism, and mitochondrial dysfunction. Abnormal mTORC1 signaling may also be involved in the etiology of sarcopenia. To better understand the role of mTORC1 signaling in the regulation of muscle metabolism, we developed an inducible muscle-specific knockout model of DEP domain-containing 5 protein (DEPDC5 mKO), which results in constitutively active mTORC1 signaling. We hypothesized that constitutively active mTORC1 signaling in skeletal muscle would alter the metabolomic and lipidomic response to an acute bout of exercise. Wild-type (WT) and DEPDC5 muscle-specific knockout (KO) mice were studied at rest and following a 1 h bout of treadmill exercise. Acute exercise induced an increased reliance on glycolytic and pentose phosphate pathway (PPP) metabolites in the muscle of mice with hyperactive mTORC1. Lipidomic analysis showed an increase in triglycerides (TGs) in KO mice. Although exercise had a pronounced effect on muscle metabolism, the genotype effect was larger, indicating that constitutively active mTORC1 signaling exerts a dominant influence on metabolic and lipidomic regulation. We conclude that increased mTORC1 signaling shifts muscle metabolism toward greater reliance on nonoxidative energy sources in response to exercise. Understanding the mechanisms responsible for these effects may lead to the development of strategies for restoring proper mTORC1 signaling in conditions such as aging and sarcopenia.NEW & NOTEWORTHY This study demonstrates that hyperactive mTORC1 alters the muscle metabolomic and lipidomic response to exercise, with genotype having a larger effect than exercise. Knockout mice exhibited an increase in reliance on glycolysis and pentose phosphate pathway and an increase in triglyceride turnover. Wild-type mice primarily showed an increase in utilization of TCA cycle and lipid metabolism intermediates.
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Affiliation(s)
- Hanna Kalenta
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Sean P Kilroe
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Trevor B Romsdahl
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Erik D Marchant
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Rosario Maroto
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
| | - Jennifer J Linares
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
- Mass Spectrometry Facility, University of Texas Medical Branch, Galveston, Texas, United States
| | - William K Russell
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States
- Mass Spectrometry Facility, University of Texas Medical Branch, Galveston, Texas, United States
| | - Blake B Rasmussen
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
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Kano R, Kusano T, Takeda R, Shirakawa H, Poole DC, Kano Y, Hoshino D. Eccentric contraction increases hydrogen peroxide levels and alters gene expression through Nox2 in skeletal muscle of male mice. J Appl Physiol (1985) 2024; 137:778-788. [PMID: 39052772 DOI: 10.1152/japplphysiol.00335.2024] [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: 05/07/2024] [Revised: 07/03/2024] [Accepted: 07/19/2024] [Indexed: 07/27/2024] Open
Abstract
Hydrogen peroxide (H2O2) is one of the key signaling factors regulating skeletal muscle adaptation to muscle contractions. Eccentric (ECC) and concentric (CONC) contractions drive different muscle adaptations with ECC resulting in greater changes. The present investigation tested the hypothesis that ECC produces higher cytosolic and mitochondrial H2O2 concentrations [H2O2] and alters gene expression more than CONC. Cytosolic and mitochondrial H2O2-sensitive fluorescent proteins, HyPer7 and MLS-HyPer7, were expressed in the anterior tibialis muscle of C57BL6J male mice. Before and for 60 min after either CONC or ECC (100 Hz, 50 contractions), [H2O2]cyto and [H2O2]mito were measured by in vivo fluorescence microscopy. RNA sequencing was performed in control (noncontracted), CONC, and ECC muscles to identify genes impacted by the contractions. [H2O2]cyto immediately after ECC was greater than after CONC (CONC: +6%, ECC: +11% vs. rest, P < 0.05) and remained higher for at least 60 min into recovery. In contrast, the elevation of [H2O2]mito was independent of the contraction modes (time; P < 0.0042, contraction mode; P = 0.4965). The impact of ECC on [H2O2]cyto was abolished by NADPH oxidase 2 (Nox2) inhibition (GSK2795039). Differentially expressed genes were not present after CONC or ECC + GSK but were found after ECC and were enriched for vascular development and apoptosis-related genes, among others. In conclusion, in mouse anterior tibialis, ECC, but not CONC, evokes a pronounced cytosolic H2O2 response, caused by Nox2, that is mechanistically linked to gene expression modifications.NEW & NOTEWORTHY This in vivo model successfully characterized the effects of eccentric (ECC) and concentric (CONC) contractions on cytosolic and mitochondrial [H2O2] in mouse skeletal muscle. Compared with CONC, ECC induced higher and more sustained [H2O2]cyto-an effect that was abolished by Nox2 inhibition. ECC-induced [H2O2]cyto elevations were requisite for altered gene expression.
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Affiliation(s)
- Ryotaro Kano
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
- Research Fellowship for Young Scientists, Japan Society for the Promotion of Science, Chiyoda, Japan
| | - Tatsuya Kusano
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
| | - Reo Takeda
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
| | - Hideki Shirakawa
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
| | - David C Poole
- Department of Anatomy and Physiology, Kansas State University, Manhattan, Kansas, United States
- Department of Kinesiology, Kansas State University, Manhattan, Kansas, United States
| | - Yutaka Kano
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
- Center for Neuroscience and Biomedical Engineering (CNBE), University of Electro-Communications, Chofu, Japan
| | - Daisuke Hoshino
- Department of Engineering Science, Bioscience and Technology Program, University of Electro-Communications, Chofu, Japan
- Center for Neuroscience and Biomedical Engineering (CNBE), University of Electro-Communications, Chofu, Japan
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Baumert P, Mäntyselkä S, Schönfelder M, Heiber M, Jacobs MJ, Swaminathan A, Minderis P, Dirmontas M, Kleigrewe K, Meng C, Gigl M, Ahmetov II, Venckunas T, Degens H, Ratkevicius A, Hulmi JJ, Wackerhage H. Skeletal muscle hypertrophy rewires glucose metabolism: An experimental investigation and systematic review. J Cachexia Sarcopenia Muscle 2024; 15:989-1002. [PMID: 38742477 PMCID: PMC11154753 DOI: 10.1002/jcsm.13468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/06/2024] [Accepted: 03/15/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy. METHODS We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level. RESULTS The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8). CONCLUSIONS Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
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Affiliation(s)
- Philipp Baumert
- School of Medicine and HealthTechnical University of MunichMunichGermany
- Research Institute for Sport and Exercise SciencesLiverpool John Moores UniversityLiverpoolUK
- Research Unit for Orthopaedic Sports Medicine and Injury Prevention (OSMI)UMIT TIROL ‐ Private University for Health Sciences and Health TechnologyInnsbruckAustria
| | - Sakari Mäntyselkä
- Faculty of Sport and Health Sciences, NeuroMuscular Research CenterUniversity of JyväskyläJyväskyläFinland
| | - Martin Schönfelder
- School of Medicine and HealthTechnical University of MunichMunichGermany
| | - Marie Heiber
- School of Medicine and HealthTechnical University of MunichMunichGermany
- Institute of Sport ScienceUniversity of the Bundeswehr MunichNeubibergGermany
| | - Mika Jos Jacobs
- School of Medicine and HealthTechnical University of MunichMunichGermany
| | - Anandini Swaminathan
- Institute of Sport Science and InnovationsLithuanian Sports UniversityKaunasLithuania
| | - Petras Minderis
- Institute of Sport Science and InnovationsLithuanian Sports UniversityKaunasLithuania
| | - Mantas Dirmontas
- Department of Health Promotion and RehabilitationLithuanian Sports UniversityKaunasLithuania
| | - Karin Kleigrewe
- Bavarian Center for Biomolecular Mass SpectrometryTechnical University of MunichMunichGermany
| | - Chen Meng
- Bavarian Center for Biomolecular Mass SpectrometryTechnical University of MunichMunichGermany
| | - Michael Gigl
- Bavarian Center for Biomolecular Mass SpectrometryTechnical University of MunichMunichGermany
| | - Ildus I. Ahmetov
- Research Institute for Sport and Exercise SciencesLiverpool John Moores UniversityLiverpoolUK
| | - Tomas Venckunas
- Institute of Sport Science and InnovationsLithuanian Sports UniversityKaunasLithuania
| | - Hans Degens
- Institute of Sport Science and InnovationsLithuanian Sports UniversityKaunasLithuania
- Department of Life SciencesManchester Metropolitan UniversityManchesterUK
| | - Aivaras Ratkevicius
- Institute of Sport Science and InnovationsLithuanian Sports UniversityKaunasLithuania
- Sports and Exercise Medicine CentreQueen Mary University of LondonLondonUK
| | - Juha J. Hulmi
- Faculty of Sport and Health Sciences, NeuroMuscular Research CenterUniversity of JyväskyläJyväskyläFinland
| | - Henning Wackerhage
- School of Medicine and HealthTechnical University of MunichMunichGermany
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Lautaoja-Kivipelto JH, Karvinen S, Korhonen TM, O'Connell TM, Tiirola M, Hulmi JJ, Pekkala S. Interaction of the C2C12 myotube contractions and glucose availability on transcriptome and extracellular vesicle microRNAs. Am J Physiol Cell Physiol 2024; 326:C348-C361. [PMID: 38047306 PMCID: PMC11192488 DOI: 10.1152/ajpcell.00401.2023] [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: 08/22/2023] [Revised: 11/26/2023] [Accepted: 11/26/2023] [Indexed: 12/05/2023]
Abstract
Exercise-like electrical pulse stimulation (EL-EPS) of myotubes mimics many key physiological changes induced by in vivo exercise. Besides enabling intracellular research, EL-EPS allows to study secreted factors, including muscle-specific microRNAs (myomiRs) carried in extracellular vesicles (EVs). These factors can participate in contraction-induced intercellular cross talk and may mediate the health benefits of exercise. However, the current knowledge of these responses, especially under variable nutritional conditions, is limited. We investigated the effects of EL-EPS on C2C12 myotube transcriptome in high- and low-glucose conditions by messenger RNA sequencing, while the expression of EV-carried miRNAs was analyzed by small RNA sequencing and RT-qPCR. We show that higher glucose availability augmented contraction-induced transcriptional changes and that the majority of the differentially expressed genes were upregulated. Furthermore, based on the pathway analyses, processes related to contractility and cytokine/inflammatory responses were upregulated. In addition, we report that EL-EPS increased packing of miR-1-3p into EVs independent of glucose availability. Together our findings suggest that in vitro EL-EPS is a usable tool not only to study contraction-induced intracellular mechanisms but also extracellular responses. The distinct transcriptional changes observed under variable nutritional conditions emphasize the importance of careful consideration of media composition in future exercise-mimicking studies.NEW & NOTEWORTHY The present study examined for the first time the effects of exercise-like electrical pulse stimulation administered under distinct nutritional conditions on 1) the transcriptome of the C2C12 myotubes and 2) their media containing extracellular vesicle-carried microRNAs. We report that higher glucose availability augmented transcriptional responses related especially to contractility and cytokine/inflammatory pathways. Agreeing with in vivo studies, we show that the packing of exercise-responsive miR-1-3p was increased in the extracellular vesicles in response to myotube contractions.
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Affiliation(s)
- Juulia H Lautaoja-Kivipelto
- Faculty of Sport and Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
- Faculty of Medicine, Research Unit of Biomedicine and Internal Medicine, University of Oulu, Oulu, Finland
| | - Sira Karvinen
- Faculty of Sport and Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - Tia-Marje Korhonen
- Faculty of Sport and Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - Thomas M O'Connell
- Department of Otolaryngology, Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Marja Tiirola
- Department of Biological and Environmental Science, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Juha J Hulmi
- Faculty of Sport and Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - Satu Pekkala
- Faculty of Sport and Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland
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Xia H, Scholtes C, Dufour CR, Guluzian C, Giguère V. ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency. Mol Metab 2023; 78:101814. [PMID: 37802398 PMCID: PMC10590867 DOI: 10.1016/j.molmet.2023.101814] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 09/20/2023] [Accepted: 09/28/2023] [Indexed: 10/10/2023] Open
Abstract
OBJECTIVE Estrogen related receptor α (ERRα) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRα on skeletal muscle exercise metabolism and performance. METHODS We recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRα impedes its degradation, leading to an accumulation of ERRα proteins and perturbation of metabolic homeostasis in ERRα3SA mutant mice. Herein, we used a multi-omics approach in combination with physical endurance tests to ascertain the consequences of expressing the constitutively active phospho-deficient ERRα3SA form on muscle exercise performance and energy metabolism. RESULTS Genetic heightening of ERRα activity enhanced exercise capacity, fatigue-resistance, and endurance. This phenotype resulted from extensive reprogramming of ERRα global DNA occupancy and transcriptome in muscle leading to an increase in oxidative fibers, mitochondrial biogenesis, fatty acid oxidation, and lactate homeostasis. CONCLUSION Our findings support the potential to enhance physical performance and exercise-induced health benefits by targeting molecular pathways regulating ERRα transcriptional activity.
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Affiliation(s)
- Hui Xia
- Goodman Cancer Institute, McGill University, Montréal, Québec, Canada H3A 1A3; Department of Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada H3G 1Y6
| | - Charlotte Scholtes
- Goodman Cancer Institute, McGill University, Montréal, Québec, Canada H3A 1A3
| | - Catherine R Dufour
- Goodman Cancer Institute, McGill University, Montréal, Québec, Canada H3A 1A3
| | - Christina Guluzian
- Goodman Cancer Institute, McGill University, Montréal, Québec, Canada H3A 1A3; Department of Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada H3G 1Y6
| | - Vincent Giguère
- Goodman Cancer Institute, McGill University, Montréal, Québec, Canada H3A 1A3; Department of Biochemistry, Faculty of Medicine and Health Sciences, McGill University, Montréal, Québec, Canada H3G 1Y6.
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Kuraji R, Shiba T, Dong TS, Numabe Y, Kapila YL. Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis. World J Gastroenterol 2023; 29:967-996. [PMID: 36844143 PMCID: PMC9950865 DOI: 10.3748/wjg.v29.i6.967] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/14/2022] [Accepted: 01/30/2023] [Indexed: 02/10/2023] Open
Abstract
A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.
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Affiliation(s)
- Ryutaro Kuraji
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-0071, Japan
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
| | - Takahiko Shiba
- Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, United States
- Department of Periodontology, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
| | - Tien S Dong
- The Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Department of Medicine, University of California David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Yukihiro Numabe
- Department of Periodontology, The Nippon Dental University School of Life Dentistry at Tokyo, Tokyo 102-8159, Japan
| | - Yvonne L Kapila
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, United States
- Sections of Biosystems and Function and Periodontics, Professor and Associate Dean of Research, Felix and Mildred Yip Endowed Chair in Dentistry, University of California Los Angeles, Los Angeles, CA 90095, United States
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Glucose 6-P Dehydrogenase—An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise. Cells 2022; 11:cells11193041. [PMID: 36231003 PMCID: PMC9563910 DOI: 10.3390/cells11193041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 11/16/2022] Open
Abstract
Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.
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The retroelement Lx9 puts a brake on the immune response to virus infection. Nature 2022; 608:757-765. [PMID: 35948641 DOI: 10.1038/s41586-022-05054-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 06/30/2022] [Indexed: 11/08/2022]
Abstract
The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago1,2. However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes3,4. The presence of DNA regulatory regions including promoters, enhancers and transcription-factor-binding sites within transposable elements5-8 has led to the hypothesis that transposable elements have been co-opted to regulate mammalian gene expression and cell phenotype8-14. Mammalian transposable elements include recent acquisitions and ancient transposable elements that have been maintained in the genome over evolutionary time. The presence of ancient conserved transposable elements correlates positively with the likelihood of a regulatory function, but functional validation remains an essential step to identify transposable element insertions that have a positive effect on fitness. Here we show that CRISPR-Cas9-mediated deletion of a transposable element-namely the LINE-1 retrotransposon Lx9c11-in mice results in an exaggerated and lethal immune response to virus infection. Lx9c11 is critical for the neogenesis of a non-coding RNA (Lx9c11-RegoS) that regulates genes of the Schlafen family, reduces the hyperinflammatory phenotype and rescues lethality in virus-infected Lx9c11-/- mice. These findings provide evidence that a transposable element can control the immune system to favour host survival during virus infection.
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Wackerhage H, Vechetti IJ, Baumert P, Gehlert S, Becker L, Jaspers RT, de Angelis MH. Does a Hypertrophying Muscle Fibre Reprogramme its Metabolism Similar to a Cancer Cell? Sports Med 2022; 52:2569-2578. [PMID: 35460513 PMCID: PMC9584876 DOI: 10.1007/s40279-022-01676-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2022] [Indexed: 02/01/2023]
Abstract
In 1924, Otto Warburg asked "How does the metabolism of a growing tissue differ from that of a non-growing tissue?" Currently, we know that proliferating healthy and cancer cells reprogramme their metabolism. This typically includes increased glucose uptake, glycolytic flux and lactate synthesis. A key function of this reprogramming is to channel glycolytic intermediates and other metabolites into anabolic reactions such as nucleotide-RNA/DNA synthesis, amino acid-protein synthesis and the synthesis of, for example, acetyl and methyl groups for epigenetic modification. In this review, we discuss evidence that a hypertrophying muscle similarly takes up more glucose and reprogrammes its metabolism to channel energy metabolites into anabolic pathways. We specifically discuss the functions of the cancer-associated enzymes phosphoglycerate dehydrogenase and pyruvate kinase muscle 2 in skeletal muscle. In addition, we ask whether increased glucose uptake by a hypertrophying muscle explains why muscularity is often negatively associated with type 2 diabetes mellitus and obesity.
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Affiliation(s)
- Henning Wackerhage
- Exercise Biology Group, Department of Health and Sports Sciences, Technical University of Munich, Munich, Germany
| | - Ivan J. Vechetti
- Department of Nutrition and Health Sciences, College of Education and Human Sciences, University of Nebraska-Lincoln, Lincoln, NE USA
| | - Philipp Baumert
- Exercise Biology Group, Department of Health and Sports Sciences, Technical University of Munich, Munich, Germany
| | - Sebastian Gehlert
- Department of Biosciences of Sports, Institute for Sports Science, University of Hildesheim, Hildesheim, Germany
| | - Lore Becker
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
| | - Richard T. Jaspers
- Laboratory for Myology, Behavioural and Movement Sciences, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Martin Hrabě de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany ,German Center for Diabetes Research (DZD), Neuherberg, Germany ,Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, Germany
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Valentino T, Figueiredo VC, Mobley CB, McCarthy JJ, Vechetti IJ. Evidence of myomiR regulation of the pentose phosphate pathway during mechanical load-induced hypertrophy. Physiol Rep 2021; 9:e15137. [PMID: 34889054 PMCID: PMC8661100 DOI: 10.14814/phy2.15137] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/13/2021] [Accepted: 11/10/2021] [Indexed: 12/29/2022] Open
Abstract
Many of the molecular and cellular mechanisms discovered to regulate skeletal muscle hypertrophy were first identified using the rodent synergist ablation model. This model reveals the intrinsic capability and necessary pathways of skeletal muscle growth in response to mechanical overload (MOV). Reminiscent of the rapid cellular growth observed with cancer, we hypothesized that in response to MOV, skeletal muscle would undergo metabolic programming to sustain increased demands to support hypertrophy. To test this hypothesis, we analyzed the gene expression of specific metabolic pathways taken from transcriptomic microarray data of a MOV time course. We found an upregulation of genes involved in the oxidative branch of the pentose phosphate pathways (PPP) and mitochondrial branch of the folate cycle suggesting an increase in the production of NADPH. In addition, we sought to determine the potential role of skeletal muscle-enriched microRNA (myomiRs) and satellite cells in the regulation of the metabolic pathways that changed during MOV. We observed an inverse pattern in gene expression between muscle-enriched myomiR-1 and its known target gene glucose-6-phosphate dehydrogenase, G6pdx, suggesting myomiR regulation of PPP activation in response to MOV. Satellite cell fusion had a significant but modest impact on PPP gene expression. These transcriptomic findings suggest the robust muscle hypertrophy induced by MOV requires enhanced redox metabolism via PPP production of NADPH which is potentially regulated by a myomiR network.
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Affiliation(s)
- Taylor Valentino
- Department of PhysiologyCollege of MedicineLexingtonKentuckyUSA
- Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
| | - Vandre C. Figueiredo
- Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
- Department of Physical TherapyCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
| | | | - John J. McCarthy
- Department of PhysiologyCollege of MedicineLexingtonKentuckyUSA
- Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
| | - Ivan J. Vechetti
- Department of Nutrition and Health SciencesCollege of Education and Human SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
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12
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Lautaoja JH, M O'Connell T, Mäntyselkä S, Peräkylä J, Kainulainen H, Pekkala S, Permi P, Hulmi JJ. Higher glucose availability augments the metabolic responses of the C2C12 myotubes to exercise-like electrical pulse stimulation. Am J Physiol Endocrinol Metab 2021; 321:E229-E245. [PMID: 34181491 PMCID: PMC8410101 DOI: 10.1152/ajpendo.00133.2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The application of exercise-like electrical pulse simulation (EL-EPS) has become a widely used exercise mimetic in vitro. EL-EPS produces similar physiological responses as in vivo exercise, while less is known about the detailed metabolic effects. Routinely, the C2C12 myotubes are cultured in high-glucose medium (4.5 g/L), which may alter EL-EPS responses. In this study, we evaluate the metabolic effects of EL-EPS under the high- and low-glucose (1.0 g/L) conditions to understand how substrate availability affects the myotube response to EL-EPS. The C2C12 myotube, media, and cell-free media metabolites were analyzed using untargeted nuclear magnetic resonance (NMR)-based metabolomics. Furthermore, translational and metabolic changes and possible exerkine effects were analyzed. EL-EPS enhanced substrate utilization as well as production and secretion of lactate, acetate, 3-hydroxybutyrate, and branched-chain fatty acids (BCFAs). The increase in BCFAs correlated with branched-chain amino acids (BCAAs) and BCFAs were strongly decreased when myotubes were cultured without BCAAs suggesting the action of acyl-CoA thioesterases on BCAA catabolites. Notably, not all EL-EPS responses were augmented by high glucose because EL-EPS increased phosphorylated c-Jun N-terminal kinase and interleukin-6 secretion independent of glucose availability. Administration of acetate and EL-EPS conditioned media on HepG2 hepatocytes had no adverse effects on lipolysis or triacylglycerol content. Our results demonstrate that unlike in cell-free media, the C2C12 myotube and media metabolites were affected by EL-EPS, particularly under high-glucose condition suggesting that media composition should be considered in future EL-EPS studies. Furthermore, acetate and BCFAs were identified as putative exerkines warranting more research.NEW & NOTEWORTHY The present study examined for the first time the metabolome of 1) C2C12 myotubes, 2) their growth media, and 3) cell-free media after exercise-like electrical pulse stimulation under distinct nutritional loads. We report that myotubes grown under high-glucose conditions had greater responsiveness to EL-EPS when compared with lower glucose availability conditions and increased media content of acetate and branched-chain fatty acids suggests they might act as putative exerkines warranting further research.
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Affiliation(s)
- Juulia H Lautaoja
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - Thomas M O'Connell
- Department of Otolaryngology-Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Sakari Mäntyselkä
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
- Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
| | - Juuli Peräkylä
- Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
| | - Heikki Kainulainen
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - Satu Pekkala
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
| | - Perttu Permi
- Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
- Department of Chemistry, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Juha J Hulmi
- Faculty of Sport and Health Sciences, NeuroMuscular Research Center, University of Jyväskylä, Jyväskylä, Finland
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Vepkhvadze TF, Vorotnikov AV, Popov DV. Electrical Stimulation of Cultured Myotubes in vitro as a Model of Skeletal Muscle Activity: Current State and Future Prospects. BIOCHEMISTRY (MOSCOW) 2021; 86:597-610. [PMID: 33993862 DOI: 10.1134/s0006297921050084] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Skeletal muscles comprise more than a third of human body mass and critically contribute to regulation of body metabolism. Chronic inactivity reduces metabolic activity and functional capacity of muscles, leading to metabolic and other disorders, reduced life quality and duration. Cellular models based on progenitor cells isolated from human muscle biopsies and then differentiated into mature fibers in vitro can be used to solve a wide range of experimental tasks. The review discusses the aspects of myogenesis dynamics and regulation, which might be important in the development of an adequate cell model. The main function of skeletal muscle is contraction; therefore, electrical stimulation is important for both successful completion of myogenesis and in vitro modeling of major processes induced in the skeletal muscle by acute or regular physical exercise. The review analyzes the drawbacks of such cellular model and possibilities for its optimization, as well as the prospects for its further application to address fundamental aspects of muscle physiology and biochemistry and explore cellular and molecular mechanisms of metabolic diseases.
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Affiliation(s)
- Tatiana F Vepkhvadze
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russia
| | - Alexander V Vorotnikov
- National Medical Research Center of Cardiology, Ministry of Healthcare of the Russian Federation, Moscow, 121552, Russia
| | - Daniil V Popov
- Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, 123007, Russia. .,Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 119991, Russia
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Multiblock metabolomics: An approach to elucidate whole-body metabolism with multiblock principal component analysis. Comput Struct Biotechnol J 2021; 19:1956-1965. [PMID: 33995897 PMCID: PMC8086023 DOI: 10.1016/j.csbj.2021.04.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 03/20/2021] [Accepted: 04/04/2021] [Indexed: 12/16/2022] Open
Abstract
“Multiblock metabolomics” elucidates the global metabolic network in a whole body. “Multiblock metabolomics” combines LC/MS-based metabolomics with multiblock PCA. “Multiblock metabolomics” highlights and elicits organ-specific metabolism. TGs with less unsaturated fatty acids were highly accumulated in the diabetic liver. Principal component analysis (PCA) is a useful tool for omics analysis to identify underlying factors and visualize relationships between biomarkers. However, this approach is limited in addressing life complexity and further improvement is required. This study aimed to develop a new approach that combines mass spectrometry-based metabolomics with multiblock PCA to elucidate the whole-body global metabolic network, thereby generating comparable metabolite maps to clarify the metabolic relationships among several organs. To evaluate the newly developed method, Zucker diabetic fatty (ZDF) rats (n = 6) were used as type 2 diabetic models and Sprague Dawley (SD) rats (n = 6) as controls. Metabolites in the heart, kidney, and liver were analyzed by capillary electrophoresis and liquid chromatography mass spectrometry, respectively, and the detected metabolites were analyzed by multiblock PCA. More than 300 metabolites were detected in the heart, kidney, and liver. When the metabolites obtained from the three organs were analyzed with multiblock PCA, the score and loading maps obtained were highly synchronized and their metabolism patterns were visually comparable. A significant finding in this study was the different expression patterns in lipid metabolism among the three organs; notably triacylglycerols with polyunsaturated fatty acids or less unsaturated fatty acids showed specific accumulation patterns depending on the organs.
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Key Words
- AMP, adenosine monophosphate
- Biomarkers
- CE/MS, capillary electrophoresis mass spectrometry
- CV, coefficient of variation
- ESI, electrospray ionization
- FABP, fatty acid-binding protein
- GC/MS, gas chromatography mass spectrometry
- LC/MS, liquid chromatography mass spectrometry
- Mass spectrometry
- Metabolomics
- Multiblock PCA
- PCA, principal component analysis
- PPAR, peroxisome proliferator-activated receptor
- QC, quality control
- SD, Sprague Dawley
- TCA, tricarboxylic acid. CoA, coenzyme A
- TG, triacylglycerol
- Type 2 Diabetes
- UPLC, ultra-performance liquid chromatography
- ZDF, Zucker diabetic fatty
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