18 results on '"Montori-Grau M"'
Search Results
2. GNIP1 E3 ubiquitin ligase is a novel player in regulating glycogen metabolism in skeletal muscle
- Author
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Universitat Rovira i Virgili, Montori-Grau M; Pedreira-Casahuga R; Boyer-Díaz Z; Lassot I; García-Martínez C; Orozco A; Cebrià J; Osorio-Conles O; Chacón M; Vendrell J; Vázquez-Carrera M; Desagher S; Jiménez-Chillarón J; Gómez-Foix A, Universitat Rovira i Virgili, and Montori-Grau M; Pedreira-Casahuga R; Boyer-Díaz Z; Lassot I; García-Martínez C; Orozco A; Cebrià J; Osorio-Conles O; Chacón M; Vendrell J; Vázquez-Carrera M; Desagher S; Jiménez-Chillarón J; Gómez-Foix A
- Abstract
Glycogenin-interacting protein 1 (GNIP1) is a tripartite motif (TRIM) protein with E3 ubiquitin ligase activity that interacts with glycogenin. These data suggest that GNIP1 could play a major role in the control of glycogen metabolism. However, direct evidence based on functional analysis remains to be obtained.The aim of this study was 1) to define the expression pattern of glycogenin-interacting protein/Tripartite motif containing protein 7 (GNIP/TRIM7) isoforms in humans, 2) to test their ubiquitin E3 ligase activity, and 3) to analyze the functional effects of GNIP1 on muscle glucose/glycogen metabolism both in human cultured cells and in vivo in mice.We show that GNIP1 was the most abundant GNIP/TRIM7 isoform in human skeletal muscle, whereas in cardiac muscle only TRIM7 was expressed. GNIP1 and TRIM7 had autoubiquitination activity in vitro and were localized in the Golgi apparatus and cytosol respectively in LHCN-M2 myoblasts. GNIP1 overexpression increased glucose uptake in LHCN-M2 myotubes. Overexpression of GNIP1 in mouse muscle in vivo increased glycogen content, glycogen synthase (GS) activity and phospho-GSK-3?/? (Ser21/9) and phospho-Akt (Ser473) content, whereas decreased GS phosphorylation in Ser640. These modifications led to decreased blood glucose levels, lactate levels and body weight, without changing whole-body insulin or glucose tolerance in mouse.GNIP1 is an ubiquitin ligase with a markedly glycogenic effect in skeletal muscle.Copyright © 2018 Elsevier Inc. All rights reserved.
- Published
- 2018
3. Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans
- Author
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Universitat Rovira i Virgili, Ceperuelo-Mallafré V; Ejarque M; Serena C; Duran X; Montori-Grau M; Rodríguez MA; Yanes O; Núñez-Roa C; Roche K; Puthanveetil P; Garrido-Sánchez L; Saez E; Tinahones FJ; Garcia-Roves PM; Gómez-Foix AM; Saltiel AR; Vendrell J; Fernández-Veledo S, Universitat Rovira i Virgili, and Ceperuelo-Mallafré V; Ejarque M; Serena C; Duran X; Montori-Grau M; Rodríguez MA; Yanes O; Núñez-Roa C; Roche K; Puthanveetil P; Garrido-Sánchez L; Saez E; Tinahones FJ; Garcia-Roves PM; Gómez-Foix AM; Saltiel AR; Vendrell J; Fernández-Veledo S
- Abstract
Objective: Glycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance. Methods: We studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts. Results: We show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 p
- Published
- 2016
4. Collagen VI and endotrophin regulate glucose homeostasis in skeletal muscle
- Author
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Rodriguez, M., primary, Osorio-Conles, O., additional, Montori-Grau, M., additional, Fernández, G., additional, Kalko, S., additional, Puigdelloses, M., additional, Jou, C., additional, Ortez, C., additional, Nascimento, A., additional, Colomer, J., additional, and Jiménez-Mallebrera, C., additional
- Published
- 2016
- Full Text
- View/download PDF
5. Glucose dependence of glycogen synthase activity regulation by GSK3 and MEK/ERK inhibitors and angiotensin-(1-7) action on these pathways in cultured human myotubes
- Author
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Montori-Grau M, Tarrats N, Osorio-Conles O, Orozco A, Serrano-Marco L, Vazquez M, and Gómez-Foix AM
- Abstract
Glycogen synthase (GS) is activated by glucose/glycogen depletion in skeletal muscle cells, but the contributing signaling pathways, including the chief GS regulator GSK3, have not been fully defined. The MEK/ERK pathway is known to regulate GSK3 and respond to glucose. The aim of this study was to elucidate the GSK3 and MEK/ERK pathway contribution to GS activation by glucose deprivation in cultured human myotubes. Moreover, we tested the glucose-dependence of GSK3 and MEK/ERK effects on GS and angiotensin (1-7) actions on these pathways. We show that glucose deprivation activated GS, but did not change phospho-GS (Ser640/1), GSK3ß activity or activity-activating phosphorylation of ERK1/2. We then treated glucose-replete and -depleted cells with SB415286, U0126, LY294 and rapamycin to inhibit GSK3, MEK1/2, PI3K and mTOR, respectively. SB415286 activated GS and decreased the relative phospho-GS (Ser640/1) level, more in glucose-depleted than -replete cells. U0126 activated GS and reduced the phospho-GS (Ser640/1) content significantly in glucose-depleted cells, while GSK3ß activity tended to increase. LY294 inactivated GS in glucose-depleted cells only, without affecting relative phospho-GS (Ser640/1) level. Rapamycin had no effect on GS activation. Angiotensin-(1-7) raised phospho-ERK1/2 but not phospho-GSK3ß (Ser9) content, while it inactivated GS and increased GS phosphorylation on Ser640/1, in glucose-replete cells. In glucose-depleted cells, angiotensin-(1-7) effects on ERK1/2 and GS were reverted, while relative phospho-GSK3ß (Ser9) content decreased. In conclusion, activation of GS by glucose deprivation is not due to GS Ser640/1 dephosphorylation, GSK3ß or ERK1/2 regulation in cultured myotubes. However, glucose depletion enhances GS activation/Ser640/1 dephosphorylation due to both GSK3 and MEK/ERK inhibition. Angiotensin-(1-7) inactivates GS in glucose-replete cells in association with ERK1/2 activation, not with GSK3 regulation, and glucose deprivation reverts both hormone effects. Thus, the ERK1/2 pathway negatively regulates GS activity in myotubes, without involving GSK3 regulation, and as a function of the presence of glucose.
- Published
- 2013
6. Expression and glycogenic effect of glycogen-targeting protein phosphatase 1 regulatory subunit G(L) in cultured human muscle
- Author
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Montori-Grau M, Guitart M, Lerin-Martinez C, Andreu AL, Newgard CB, García-Martínez C, and Gómez-Foix AM
- Published
- 2007
7. P.341 - Collagen VI and endotrophin regulate glucose homeostasis in skeletal muscle
- Author
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Rodriguez, M., Osorio-Conles, O., Montori-Grau, M., Fernández, G., Kalko, S., Puigdelloses, M., Jou, C., Ortez, C., Nascimento, A., Colomer, J., and Jiménez-Mallebrera, C.
- Published
- 2016
- Full Text
- View/download PDF
8. Plasma PTX3 protein levels inversely correlate with insulin secretion and obesity, whereas visceral adipose tissue PTX3 gene expression is increased in obesity
- Author
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Osorio-Conles, O., primary, Guitart, M., additional, Chacón, M. R., additional, Maymo-Masip, E., additional, Moreno-Navarrete, J. M., additional, Montori-Grau, M., additional, Näf, S., additional, Fernandez-Real, J. M., additional, Vendrell, J., additional, and Gómez-Foix, A. M., additional
- Published
- 2011
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- View/download PDF
9. Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ.
- Author
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Zhang M, Barroso E, Ruart M, Peña L, Peyman M, Aguilar-Recarte D, Montori-Grau M, Rada P, Cugat C, Montironi C, Zarei M, Jurado-Aguilar J, Camins A, Balsinde J, Valverde ÁM, Wahli W, Palomer X, and Vázquez-Carrera M
- Subjects
- Animals, Mice, Rats, Diet, High-Fat, Epithelial-Mesenchymal Transition, Liver, Non-alcoholic Fatty Liver Disease metabolism, PPAR delta metabolism, PPAR-beta agonists, PPAR-beta metabolism, PPAR-beta therapeutic use
- Abstract
Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program., Competing Interests: Declaration of Competing Interest none'., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
- Full Text
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10. Striking a gut-liver balance for the antidiabetic effects of metformin.
- Author
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Barroso E, Montori-Grau M, Wahli W, Palomer X, and Vázquez-Carrera M
- Subjects
- Humans, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Liver, Glucose, Metformin pharmacology, Metformin therapeutic use, Diabetes Mellitus, Type 2 drug therapy
- Abstract
Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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11. Endoplasmic reticulum stress downregulates PGC-1α in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2.
- Author
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Montori-Grau M, Aguilar-Recarte D, Zarei M, Pizarro-Delgado J, Palomer X, and Vázquez-Carrera M
- Subjects
- Animals, Down-Regulation, Mice, Muscle Fibers, Skeletal metabolism, Tunicamycin metabolism, Tunicamycin pharmacology, Activating Transcription Factor 4 metabolism, Diabetes Mellitus, Type 2 metabolism, Endoplasmic Reticulum Stress, Muscle, Skeletal metabolism, TOR Serine-Threonine Kinases metabolism, Transcription Factors metabolism
- Abstract
Background: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved., Methods: The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used., Results: Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin., Conclusions: Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. Video Abstract., (© 2022. The Author(s).)
- Published
- 2022
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12. GNIP1 E3 ubiquitin ligase is a novel player in regulating glycogen metabolism in skeletal muscle.
- Author
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Montori-Grau M, Pedreira-Casahuga R, Boyer-Díaz Z, Lassot I, García-Martínez C, Orozco A, Cebrià J, Osorio-Conles O, Chacón MR, Vendrell J, Vázquez-Carrera M, Desagher S, Jiménez-Chillarón JC, and Gómez-Foix AM
- Subjects
- Animals, Cells, Cultured, HEK293 Cells, Humans, Mice, Muscle Fibers, Skeletal metabolism, Muscle, Skeletal pathology, Tripartite Motif Proteins, Ubiquitin-Protein Ligases physiology, Carrier Proteins physiology, Glycogen metabolism, Muscle, Skeletal metabolism
- Abstract
Background: Glycogenin-interacting protein 1 (GNIP1) is a tripartite motif (TRIM) protein with E3 ubiquitin ligase activity that interacts with glycogenin. These data suggest that GNIP1 could play a major role in the control of glycogen metabolism. However, direct evidence based on functional analysis remains to be obtained., Objectives: The aim of this study was 1) to define the expression pattern of glycogenin-interacting protein/Tripartite motif containing protein 7 (GNIP/TRIM7) isoforms in humans, 2) to test their ubiquitin E3 ligase activity, and 3) to analyze the functional effects of GNIP1 on muscle glucose/glycogen metabolism both in human cultured cells and in vivo in mice., Results: We show that GNIP1 was the most abundant GNIP/TRIM7 isoform in human skeletal muscle, whereas in cardiac muscle only TRIM7 was expressed. GNIP1 and TRIM7 had autoubiquitination activity in vitro and were localized in the Golgi apparatus and cytosol respectively in LHCN-M2 myoblasts. GNIP1 overexpression increased glucose uptake in LHCN-M2 myotubes. Overexpression of GNIP1 in mouse muscle in vivo increased glycogen content, glycogen synthase (GS) activity and phospho-GSK-3α/β (Ser21/9) and phospho-Akt (Ser473) content, whereas decreased GS phosphorylation in Ser640. These modifications led to decreased blood glucose levels, lactate levels and body weight, without changing whole-body insulin or glucose tolerance in mouse., Conclusion: GNIP1 is an ubiquitin ligase with a markedly glycogenic effect in skeletal muscle., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
13. PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders.
- Author
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Palomer X, Barroso E, Pizarro-Delgado J, Peña L, Botteri G, Zarei M, Aguilar D, Montori-Grau M, and Vázquez-Carrera M
- Subjects
- Animals, Humans, Metabolic Diseases drug therapy, Metabolic Diseases metabolism, Molecular Targeted Therapy methods, PPAR delta genetics, PPAR delta metabolism, PPAR-beta genetics, PPAR-beta metabolism, Metabolic Diseases genetics, PPAR delta agonists, PPAR-beta agonists
- Abstract
Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARβ/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARβ/δ as a treatment for human metabolic disorders., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
- Full Text
- View/download PDF
14. Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans.
- Author
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Ceperuelo-Mallafré V, Ejarque M, Serena C, Duran X, Montori-Grau M, Rodríguez MA, Yanes O, Núñez-Roa C, Roche K, Puthanveetil P, Garrido-Sánchez L, Saez E, Tinahones FJ, Garcia-Roves PM, Gómez-Foix AM, Saltiel AR, Vendrell J, and Fernández-Veledo S
- Abstract
Objective: Glycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance., Methods: We studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts., Results: We show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 phenotype. Increased glycogen synthase expression correlates with glycogen deposition in subcutaneous adipose tissue of obese patients. Glycogen content in subcutaneous mature adipocytes is associated with BMI and leptin expression., Conclusion: Our data establish glycogen mishandling in adipose tissue as a potential key feature of inflammatory-related metabolic stress in human obesity.
- Published
- 2015
- Full Text
- View/download PDF
15. Plasma PTX3 protein levels inversely correlate with insulin secretion and obesity, whereas visceral adipose tissue PTX3 gene expression is increased in obesity.
- Author
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Osorio-Conles O, Guitart M, Chacón MR, Maymo-Masip E, Moreno-Navarrete JM, Montori-Grau M, Näf S, Fernandez-Real JM, Vendrell J, and Gómez-Foix AM
- Subjects
- Adipocytes drug effects, Adipocytes metabolism, Adipocytes pathology, Adult, Aged, C-Reactive Protein metabolism, Cells, Cultured, Cohort Studies, Cytokines pharmacology, Female, Gene Expression Regulation drug effects, Humans, Infant, Inflammation Mediators pharmacology, Insulin Secretion, Intra-Abdominal Fat drug effects, Male, Middle Aged, Obesity genetics, Obesity pathology, Serum Amyloid P-Component metabolism, Up-Regulation drug effects, C-Reactive Protein analysis, C-Reactive Protein genetics, Insulin metabolism, Intra-Abdominal Fat metabolism, Obesity blood, Obesity metabolism, Serum Amyloid P-Component analysis, Serum Amyloid P-Component genetics
- Abstract
Plasma acutephase protein pentraxin 3 (PTX3) concentration is dysregulated in human obesity and metabolic syndrome. Here, we explore its relationship with insulin secretion and sensitivity, obesity markers, and adipose tissue PTX3 gene expression. Plasma PTX3 protein levels were analyzed in a cohort composed of 27 lean [body mass index (BMI) ≤ 25 kg/m(2)] and 48 overweight (BMI 25-30 kg/m(2)) men (cohort 1). In this cohort, plasma PTX3 was negatively correlated with fasting triglyceride levels and insulin secretion after intravenous and oral glucose administration. Plasma PTX3 protein and PTX3 gene expression in visceral (VAT) and subcutaneous (SAT) whole adipose tissue and adipocyte and stromovascular fractions were analyzed in cohort 2, which was composed of 19 lean, 28 overweight, and 15 obese subjects (BMI >30 kg/m(2)). An inverse association with body weight and waist/hip ratio was observed in cohort 2. In VAT depots, PTX3 mRNA levels were higher in subjects with BMI >25 kg/m(2) than in lean subjects, positively correlated with IL-1β mRNA levels, and higher in the adipocyte than stromovascular fraction. Human preadipocyte SGBS cell line was used to study PTX3 production in response to factors that obesity entails. In SGBS adipocytes, PTX3 gene expression was enhanced by IL-1β and TNFα but not IL-6 or insulin. In conclusion, the negative correlation between PTX3 and glucose-stimulated insulin secretion suggests a role for PTX3 in metabolic control. PTX3 gene expression is upregulated in VAT depots in obesity, despite lower plasma PTX3 protein, and by some proinflammatory cytokines in cultured adipocytes.
- Published
- 2011
- Full Text
- View/download PDF
16. Differential pattern of glycogen accumulation after protein phosphatase 1 glycogen-targeting subunit PPP1R6 overexpression, compared to PPP1R3C and PPP1R3A, in skeletal muscle cells.
- Author
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Montori-Grau M, Guitart M, García-Martínez C, Orozco A, and Gómez-Foix AM
- Subjects
- Animals, Carrier Proteins genetics, Cytosol metabolism, ErbB Receptors genetics, Gene Expression Regulation, Glycogen biosynthesis, Glycogen Phosphorylase metabolism, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Microfilament Proteins genetics, Muscle Fibers, Skeletal metabolism, Muscle Fibers, Skeletal ultrastructure, Muscle, Skeletal cytology, Muscle, Skeletal ultrastructure, Nerve Tissue Proteins genetics, Phosphoprotein Phosphatases genetics, Phosphorylation, Signal Transduction, Carrier Proteins metabolism, ErbB Receptors metabolism, Glycogen metabolism, Glycogen ultrastructure, Microfilament Proteins metabolism, Nerve Tissue Proteins metabolism, Phosphoprotein Phosphatases metabolism
- Abstract
Background: PPP1R6 is a protein phosphatase 1 glycogen-targeting subunit (PP1-GTS) abundant in skeletal muscle with an undefined metabolic control role. Here PPP1R6 effects on myotube glycogen metabolism, particle size and subcellular distribution are examined and compared with PPP1R3C/PTG and PPP1R3A/G(M)., Results: PPP1R6 overexpression activates glycogen synthase (GS), reduces its phosphorylation at Ser-641/0 and increases the extracted and cytochemically-stained glycogen content, less than PTG but more than G(M). PPP1R6 does not change glycogen phosphorylase activity. All tested PP1-GTS-cells have more glycogen particles than controls as found by electron microscopy of myotube sections. Glycogen particle size is distributed for all cell-types in a continuous range, but PPP1R6 forms smaller particles (mean diameter 14.4 nm) than PTG (36.9 nm) and G(M) (28.3 nm) or those in control cells (29.2 nm). Both PPP1R6- and G(M)-derived glycogen particles are in cytosol associated with cellular structures; PTG-derived glycogen is found in membrane- and organelle-devoid cytosolic glycogen-rich areas; and glycogen particles are dispersed in the cytosol in control cells. A tagged PPP1R6 protein at the C-terminus with EGFP shows a diffuse cytosol pattern in glucose-replete and -depleted cells and a punctuate pattern surrounding the nucleus in glucose-depleted cells, which colocates with RFP tagged with the Golgi targeting domain of β-1,4-galactosyltransferase, according to a computational prediction for PPP1R6 Golgi location., Conclusions: PPP1R6 exerts a powerful glycogenic effect in cultured muscle cells, more than G(M) and less than PTG. PPP1R6 protein translocates from a Golgi to cytosolic location in response to glucose. The molecular size and subcellular location of myotube glycogen particles is determined by the PPP1R6, PTG and G(M) scaffolding.
- Published
- 2011
- Full Text
- View/download PDF
17. Effects of aging and calorie restriction on rat skeletal muscle glycogen synthase and glycogen phosphorylase.
- Author
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Montori-Grau M, Minor R, Lerin C, Allard J, Garcia-Martinez C, de Cabo R, and Gómez-Foix AM
- Subjects
- Aging metabolism, Animals, Blotting, Western, Caloric Restriction, Male, Rats, Aging physiology, Glycogen Phosphorylase metabolism, Glycogen Synthase metabolism, Muscle, Skeletal physiology
- Abstract
Calorie restriction's (CR) effects on age-associated changes in glycogen-metabolizing enzymes were studied in rat soleus (SOL) and tibialis anterior (TA) muscles. Old (24 months) compared to young (6 months) rats maintained ad libitum on a standard diet had reduced glycogen synthase (GS) activity, lower muscle GS protein levels, increased phosphorylation of GS at site 3a with less activation in SOL. Age-associated impairments in GS protein and activation-phosphorylation were also shown in TA. There was an age-associated reduction in glycogen phosphorylase (GP) activity level in SOL, while brain/muscle isoforms (B/M) of GP protein levels were higher. GP activity and protein levels were preserved, but GP was inactivated in TA with age. Glycogen content was unchanged in both muscles. CR did not alter GS or GP activity/protein levels in young rats. CR hindered age-related decreases in GS activity/protein, unrelated to GS mRNA levels, and GS inactivation-phosphorylation; not on GP. In older rats, CR enhanced glycogen accumulation in SOL. Short-term fasting did not recapitulate CR effects in old rats. Thus, the predominant age-associated impairments on skeletal muscle GS and GP activities occur in the oxidative SOL muscle of rats, and CR can attenuate the loss of GS activity/activation and stimulate glycogen accumulation.
- Published
- 2009
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18. Long-term cultured human myotubes decrease contractile gene expression and regulate apoptosis-related genes.
- Author
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Ferrer-Martínez A, Montell E, Montori-Grau M, García-Martínez C, Gómez-Foix AM, Roberts MA, Mansourian R, and Macé K
- Subjects
- Adolescent, Biopsy, Cell Culture Techniques, Cell Survival genetics, Cells, Cultured, Child, Down-Regulation, Gene Expression Profiling, Glucose metabolism, Humans, Lipid Metabolism genetics, Membrane Potential, Mitochondrial, Muscles cytology, Muscles pathology, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Time, Apoptosis genetics, Muscle Fibers, Skeletal metabolism, Muscle Proteins genetics
- Abstract
The present study examined time-dependent changes in the gene expression profile of long-term cultured human myotubes. Microarray transcriptional analysis was performed in a primary culture of differentiated myotubes from one subject over seven weeks. This analysis showed a main gradual fall in genes of the contractile apparatus, and a broad upregulation of genes involved in cell development and growth, followed by stress response and signal transduction. Glucose metabolism was also monitored, but no significant alterations in glucose uptake, oxidation or glycogen storage were observed. Mitochondrial membrane potential, or the amount of membrane lipid peroxides, remained similarly unchanged, nor was lactate dehydrogenase leakage observed. Time-dependent changes in eight genes were validated by real-time RT-PCR in primary cultured myotubes from four subjects, of similar age and isolated after equivalent replication cycles in vitro and differentiated over seven weeks. Insulin-like growth factor-binding protein 2 (IGFBP2), a modulator of the IGF signal, was upregulated. The antiapoptotic gene heat-shock 70-kd protein 2 (HSPA2) was induced, whereas the proapoptotic tumor necrosis factor receptor superfamily, member 25 (WSL-1) was suppressed. A decline in the muscle-specific gene M-cadherin and contraction genes, such as slow-twitch troponin I (TNNI1) and myosin heavy chain 2 (MYH2), myosin light chain 1 (MYL1) and myosin-binding protein H (MYBPH), which are expressed in adult fast-twitch muscle, was shown. In summary, these data demonstrate extensive downregulation of contractile genes and modulation of apoptosis-related genes, in favour of cell survival, during maintenance of cultured human myotubes.
- Published
- 2006
- Full Text
- View/download PDF
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