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1.
HLA ; 103(1): e15252, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37848366

RESUMO

T cell therapy strategies, from allogeneic stem cell transplantation toward genetically-modified T cells infusion, develop powerful anti-tumor effects but are often accompanied by side effects and their efficacy remains sometimes to be improved. It therefore appears important to provide a flexible and easily reversible gene expression regulation system to control T cells activity. We developed a gene expression regulation technology that exploits the physiological GCN2-ATF4 pathway's ability to induce gene expression in T cells in response to one essential amino acid deficiency. We first demonstrated the functionality of NUTRIREG in human T cells by transient expression of reporter genes. We then validated that NUTRIREG can be used in human T cells to transiently express a therapeutic gene such as IL-10. Overall, our results represent a solid basis for the promising use of NUTRIREG to regulate transgene expression in human T cells in a reversible way, and more generally for numerous preventive or curative therapeutic possibilities in cellular immunotherapy strategies.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante Homólogo , Aminoácidos , Alelos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T , Transgenes
2.
Cells ; 12(1)2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36611981

RESUMO

Autophagy is an evolutionarily conserved catabolic process and represents a field of research that is constantly growing [...].


Assuntos
Autofagia , Humanos
3.
Crit Rev Food Sci Nutr ; 63(32): 11185-11210, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35730212

RESUMO

Impairment of gut function is one of the explanatory mechanisms of health status decline in elderly population. These impairments involve a decline in gut digestive physiology, metabolism and immune status, and associated to that, changes in composition and function of the microbiota it harbors. Continuous deteriorations are generally associated with the development of systemic dysregulations and ultimately pathologies that can worsen the initial health status of individuals. All these alterations observed at the gut level can then constitute a wide range of potential targets for development of nutritional strategies that can impact gut tissue or associated microbiota pattern. This can be key, in a preventive manner, to limit gut functionality decline, or in a curative way to help maintaining optimum nutrients bioavailability in a context on increased requirements, as frequently observed in pathological situations. The aim of this review is to give an overview on the alterations that can occur in the gut during aging and lead to the development of altered function in other tissues and organs, ultimately leading to the development of pathologies. Subsequently is discussed how nutritional strategies that target gut tissue and gut microbiota can help to avoid or delay the occurrence of aging-related pathologies.


Assuntos
Microbioma Gastrointestinal , Doenças Metabólicas , Microbiota , Humanos , Idoso , Envelhecimento/fisiologia , Doenças Metabólicas/prevenção & controle , Microbioma Gastrointestinal/fisiologia , Valor Nutritivo
4.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35806203

RESUMO

Chronic treatment with acetaminophen (APAP) induces cysteine (Cys) and glutathione (GSH) deficiency which leads to adverse metabolic effects including muscle atrophy. Mammalian cells respond to essential amino acid deprivation through the phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). Phosphorylated eIF2α leads to the recruitment of activating transcription factor 4 (ATF4) to specific CCAAT/enhancer-binding protein-ATF response element (CARE) located in the promoters of target genes. Our purpose was to study the activation of the eIF2α-ATF4 pathway in response to APAP-induced Cys deficiency, as well as the potential contribution of the eIF2α kinase GCN2 and the effect of dietary supplementation with Cys. Our results showed that chronic treatment with APAP activated both GCN2 and PERK eIF2α kinases and downstream target genes in the liver. Activation of the eIF2α-ATF4 pathway in skeletal muscle was accompanied by muscle atrophy even in the absence of GCN2. The dietary supplementation with cysteine reversed APAP-induced decreases in plasma-free Cys, liver GSH, muscle mass, and muscle GSH. Our new findings demonstrate that dietary Cys supplementation also reversed the APAP-induced activation of GCN2 and PERK and downstream ATF4-target genes in the liver.


Assuntos
Fator 4 Ativador da Transcrição , Fator de Iniciação 2 em Eucariotos , Acetaminofen/efeitos adversos , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Cisteína/metabolismo , Suplementos Nutricionais , Fator de Iniciação 2 em Eucariotos/metabolismo , Glutationa/metabolismo , Mamíferos/metabolismo , Atrofia Muscular/induzido quimicamente , Fosforilação , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
5.
Int J Mol Sci ; 23(7)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35409073

RESUMO

Middle-aged and master endurance athletes exhibit similar physical performance and long-term muscle adaptation to aerobic exercise. Nevertheless, we hypothesized that the short-term plasticity of the skeletal muscle might be distinctly altered for master athletes when they are challenged by a single bout of prolonged moderate-intensity exercise. Six middle-aged (37Y) and five older (50Y) master highly-trained athletes performed a 24-h treadmill run (24TR). Vastus lateralis muscle biopsies were collected before and after the run and assessed for proteomics, fiber morphometry, intramyocellular lipid droplets (LD), mitochondrial oxidative activity, extracellular matrix (ECM), and micro-vascularisation. Before 24TR, muscle fiber type morphometry, intramyocellular LD, oxidative activity, ECM and micro-vascularisation were similar between master and middle-aged runners. For 37Y runners, 24TR was associated with ECM thickening, increased capillary-to-fiber interface, and an 89% depletion of LD in type-I fibers. In contrast, for 50Y runners, 24TR did not alter ECM and capillarization and poorly depleted LDs. Moreover, an impaired succinate dehydrogenase activity and functional class scoring of proteomes suggested reduced oxidative phosphorylation post-24TR exclusively in 50Y muscle. Collectively, our data support that middle-aged and master endurance athletes exhibit distinct transient plasticity in response to a single bout of ultra-endurance exercise, which may constitute early signs of muscle aging for master athletes.


Assuntos
Atletas , Resistência Física , Envelhecimento/fisiologia , Exercício Físico/fisiologia , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Resistência Física/fisiologia
6.
Int J Mol Sci ; 24(1)2022 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-36614063

RESUMO

Activating transcription factor 4 (ATF4) is involved in muscle atrophy through the overexpression of some atrogenes. However, it also controls the transcription of genes involved in muscle homeostasis maintenance. Here, we explored the effect of ATF4 activation by the pharmacological molecule halofuginone during hindlimb suspension (HS)-induced muscle atrophy. Firstly, we reported that periodic activation of ATF4-regulated atrogenes (Gadd45a, Cdkn1a, and Eif4ebp1) by halofuginone was not associated with muscle atrophy in healthy mice. Secondly, halofuginone-treated mice even showed reduced atrophy during HS, although the induction of the ATF4 pathway was identical to that in untreated HS mice. We further showed that halofuginone inhibited transforming growth factor-ß (TGF-ß) signalling, while promoting bone morphogenetic protein (BMP) signalling in healthy mice and slightly preserved protein synthesis during HS. Finally, ATF4-regulated atrogenes were also induced in the atrophy-resistant muscles of hibernating brown bears, in which we previously also reported concurrent TGF-ß inhibition and BMP activation. Overall, we show that ATF4-induced atrogenes can be uncoupled from muscle atrophy. In addition, our data also indicate that halofuginone can control the TGF-ß/BMP balance towards muscle mass maintenance. Whether halofuginone-induced BMP signalling can counteract the effect of ATF4-induced atrogenes needs to be further investigated and may open a new avenue to fight muscle atrophy. Finally, our study opens the way for further studies to identify well-tolerated chemical compounds in humans that are able to fine-tune the TGF-ß/BMP balance and could be used to preserve muscle mass during catabolic situations.


Assuntos
Fator 4 Ativador da Transcrição , Atrofia Muscular , Ursidae , Animais , Camundongos , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Hibernação
7.
Cells ; 10(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440643

RESUMO

Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of induced atrophy, the unloaded mouse. Using RNA sequencing, we identified 4415 differentially expressed genes, including 1746 up- and 2369 down-regulated genes, in bear muscles between the active versus hibernating period. We focused on the Transforming Growth Factor (TGF)-ß and the Bone Morphogenetic Protein (BMP) pathways, respectively, involved in muscle mass loss and maintenance. TGF-ß- and BMP-related genes were overall down- and up-regulated in the non-atrophied muscles of the hibernating bear, respectively, and the opposite occurred for the atrophied muscles of the unloaded mouse. This was further substantiated at the protein level. Our data suggest TGF-ß/BMP balance is crucial for muscle mass maintenance during long-term physical inactivity in the hibernating bear. Thus, concurrent activation of the BMP pathway may potentiate TGF-ß inhibiting therapies already targeted to prevent muscle atrophy.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Hibernação , Atrofia Muscular/metabolismo , Músculo Quadríceps/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ursidae/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Elevação dos Membros Posteriores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atrofia Muscular/genética , Atrofia Muscular/patologia , Músculo Quadríceps/patologia , RNA-Seq , Transdução de Sinais , Fatores de Tempo , Transcriptoma , Fator de Crescimento Transformador beta/genética , Ursidae/genética
8.
Cells ; 10(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34440743

RESUMO

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (KD = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (KD = 46.7 nM) over monomeric G-actin (KD = 450 nM). By contrast with actin that did not alter MuRF1-UBE2L3 affinity, binding of MHC to MuRF1 (KD = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy.


Assuntos
Actinas/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Linhagem Celular , Dexametasona/farmacologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitina-Proteína Ligases/metabolismo
9.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921590

RESUMO

(1) Background: Aging is associated with a progressive decline in muscle mass and function. Aging is also a primary risk factor for metabolic syndrome, which further alters muscle metabolism. However, the molecular mechanisms involved remain to be clarified. Herein we performed omic profiling to decipher in muscle which dominating processes are associated with healthy aging and metabolic syndrome in old men. (2) Methods: This study included 15 healthy young, 15 healthy old, and 9 old men with metabolic syndrome. Old men were selected from a well-characterized cohort, and each vastus lateralis biopsy was used to combine global transcriptomic and proteomic analyses. (3) Results: Over-representation analysis of differentially expressed genes (ORA) and functional class scoring of pathways (FCS) indicated that healthy aging was mainly associated with upregulations of apoptosis and immune function and downregulations of glycolysis and protein catabolism. ORA and FCS indicated that with metabolic syndrome the dominating biological processes were upregulation of proteolysis and downregulation of oxidative phosphorylation. Proteomic profiling matched 586 muscle proteins between individuals. The proteome of healthy aging revealed modifications consistent with a fast-to-slow transition and downregulation of glycolysis. These transitions were reduced with metabolic syndrome, which was more associated with alterations in NADH/NAD+ shuttle and ß-oxidation. Proteomic profiling further showed that all old muscles overexpressed protein chaperones to preserve proteostasis and myofiber integrity. There was also evidence of aging-related increases in reactive oxygen species but better detoxifications of cytotoxic aldehydes and membrane protection in healthy than in metabolic syndrome muscles. (4) Conclusions: Most candidate proteins and mRNAs identified herein constitute putative muscle biomarkers of healthy aging and metabolic syndrome in old men.


Assuntos
Síndrome Metabólica/metabolismo , Proteômica/métodos , Animais , Glicólise/genética , Glicólise/fisiologia , Humanos , Síndrome Metabólica/genética , Músculo Esquelético/metabolismo , Sarcopenia/genética , Sarcopenia/metabolismo , Transcriptoma/genética
10.
Nutrients ; 13(3)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673609

RESUMO

Obesity, a major public health problem, is the consequence of an excess of body fat and biological alterations in the adipose tissue. Our aim was to determine whether high-intensity interval training (HIIT) and/or α-linolenic acid supplementation (to equilibrate the n-6/n-3 polyunsaturated fatty acids (PUFA) ratio) might prevent obesity disorders, particularly by modulating the mucosa-associated microbiota. Wistar rats received a low fat diet (LFD; control) or high fat diet (HFD) for 16 weeks to induce obesity. Then, animals in the HFD group were divided in four groups: HFD (control), HFD + linseed oil (LO), HFD + HIIT, HFD + HIIT + LO. In the HIIT groups, rats ran on a treadmill, 4 days.week-1. Erythrocyte n-3 PUFA content, body composition, inflammation, and intestinal mucosa-associated microbiota composition were assessed after 12 weeks. LO supplementation enhanced α-linolenic acid (ALA) to docosahexaenoic acid (DHA) conversion in erythrocytes, and HIIT potentiated this conversion. Compared with HFD, HIIT limited weight gain, fat mass accumulation, and adipocyte size, whereas LO reduced systemic inflammation. HIIT had the main effect on gut microbiota ß-diversity, but the HIIT + LO association significantly increased Oscillospira relative abundance. In our conditions, HIIT had a major effect on body fat mass, whereas HIIT + LO improved ALA conversion to DHA and increased the abundance of Oscillospira bacteria in the microbiota.


Assuntos
Clostridiales/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/metabolismo , Condicionamento Físico Animal , Ácido alfa-Linolênico/farmacologia , Adipócitos , Animais , Glicemia , Composição Corporal , Eritrócitos , Ácidos Graxos , Ácidos Graxos Voláteis/química , Fezes/química , Microbioma Gastrointestinal , Teste de Tolerância a Glucose , Treinamento Intervalado de Alta Intensidade , Mucosa Intestinal , Distribuição Aleatória , Ratos , Ratos Wistar , Ácido alfa-Linolênico/administração & dosagem
11.
Molecules ; 26(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466753

RESUMO

Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in muscle atrophy and the E3 ligases implicated, but also the molecules potentially usable for future therapies.


Assuntos
Atrofia Muscular/enzimologia , Atrofia Muscular/fisiopatologia , Biossíntese de Proteínas , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Animais , Humanos , Transdução de Sinais
12.
Front Zool ; 17(1): 35, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33292302

RESUMO

In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears (Ursus arctos), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear's peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment.

13.
Int J Mol Sci ; 21(10)2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32456262

RESUMO

Mitochondria alterations are a classical feature of muscle immobilization, and autophagy is required for the elimination of deficient mitochondria (mitophagy) and the maintenance of muscle mass. We focused on the regulation of mitochondrial quality control during immobilization and remobilization in rat gastrocnemius (GA) and tibialis anterior (TA) muscles, which have very different atrophy and recovery kinetics. We studied mitochondrial biogenesis, dynamic, movement along microtubules, and addressing to autophagy. Our data indicated that mitochondria quality control adapted differently to immobilization and remobilization in GA and TA muscles. Data showed i) a disruption of mitochondria dynamic that occurred earlier in the immobilized TA, ii) an overriding role of mitophagy that involved Parkin-dependent and/or independent processes during immobilization in the GA and during remobilization in the TA, and iii) increased mitochondria biogenesis during remobilization in both muscles. This strongly emphasized the need to consider several muscle groups to study the mechanisms involved in muscle atrophy and their ability to recover, in order to provide broad and/or specific clues for the development of strategies to maintain muscle mass and improve the health and quality of life of patients.


Assuntos
Mitocôndrias Musculares/metabolismo , Mitofagia , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Animais , Masculino , Atividade Motora , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Ratos , Ratos Wistar , Restrição Física/efeitos adversos
14.
Oxid Med Cell Longev ; 2019: 1965364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396298

RESUMO

BACKGROUND AND AIM: Exercise is an effective strategy to reduce obesity-induced oxidative stress. The purpose of this study was to compare the effects of two training modalities (moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT)) on the pro/antioxidant status of different tissues in obese Zucker rats. METHODS: Eight-week-old male Zucker rats (fa/fa, n = 36) were subdivided in three groups: MICT, HIIT, and control (no exercise) groups. Trained animals ran on a treadmill (0° slope), 5 days/week for 10 weeks (MICT: 51 min at 12 m·min-1; HIIT: 6 sets of 3 min at 10 m·min-1 followed by 4 min at 18 m·min-1). Epididymal (visceral) and subcutaneous adipose tissue, gastrocnemius muscle, and plasma samples were collected to measure oxidative stress markers (advanced oxidation protein products (AOPP), oxidized low-density lipoprotein (oxLDL)), antioxidant system markers (ferric-reducing ability of plasma (FRAP), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) activities), and prooxidant enzymes (NADPH oxidase and xanthine oxidase (XO) activities, myeloperoxidase content). RESULTS: Compared with the control, MICT increased GPx and catalase activities and the FRAP level in epididymal adipose tissue. HIIT increased the AOPP level in subcutaneous adipose tissue. In the muscle, HIIT increased both SOD and GPx activities and reduced the AOPP level, whereas MICT increased only SOD activity. Finally, plasma myeloperoxidase content was similarly decreased by both training modalities, whereas oxLDL was reduced only in the MICT group. CONCLUSION: Both HIIT and MICT improved the pro/antioxidant status. However, HIIT was more efficient than MICT in the skeletal muscle, whereas MICT was more efficient in epididymal adipose tissue. This suggests that oxidative stress responses to HIIT and MICT are tissue-specific. This could result in ROS generation via different pathways in these tissues. From a practical point of view, the two training modalities should be combined to obtain a global response in people with obesity.


Assuntos
Tecido Adiposo/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Condicionamento Físico Animal , Animais , Antioxidantes/metabolismo , Glutationa Peroxidase/metabolismo , Treinamento Intervalado de Alta Intensidade , Lipoproteínas LDL/sangue , Masculino , Malondialdeído/sangue , NADPH Oxidases/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Oxidantes/metabolismo , Ratos , Ratos Zucker , Superóxido Dismutase/metabolismo
15.
PLoS One ; 14(4): e0214660, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964881

RESUMO

AIMS: Increased visceral adipose tissue and dysbiosis in the overweight and obese promote chronic inflammation. The aim of this study was to compare the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on the gut-adipose tissue cross-talk in obese Zucker rats. METHODS: Obese male Zucker rats (n = 36) were divided in three groups: MICT (12m.min-1 for 51min), HIIT (6 sets at 18 m.min-1 for 4min followed by 3min at 10m.min-1) and controls (CONT; no exercise). The animals ran on a treadmill 5 days/week for 10 weeks. Body composition, glycaemic control, lipid profile, inflammation, lipolysis signalling in subcutaneous and visceral adipose tissue, intestinal permeability (tight junctions and plasma lipopolysaccharide binding protein; LBP), and gut microbiota composition were assessed in the three groups. RESULTS: After 10 weeks of exercise, total and epididymal fat mass decreased only in the HIIT group. The α/ß adrenergic receptor RNA ratio in subcutaneous adipose tissue increased only in the HIIT group. The expression level of phosphorylated hormone-sensitive lipase was not modified by training. Both HIIT and MICT decreased inflammation (plasma myeloperoxidase and keratinocyte-derived chemokine secretion in adipose tissue) and improved glucose metabolism. Zonula occludens-1 and occludin were upregulated in the HIIT group. Plasma LBP was similarly reduced in both training groups. HIIT and MICT did not affect gut microbiota composition. CONCLUSION: In obese Zucker rats, HIIT and MICT improved inflammation and glucose metabolism. In contrast, only HIIT decreased total and visceral fat mass. These adaptations were not associated with modifications in gut microbiota composition.


Assuntos
Gordura Intra-Abdominal/metabolismo , Condicionamento Físico Animal , Proteínas de Fase Aguda , Animais , Composição Corporal , Proteínas de Transporte/sangue , Metabolismo Energético , Microbioma Gastrointestinal , Regulação da Expressão Gênica , Glucose/metabolismo , Masculino , Glicoproteínas de Membrana/sangue , Ocludina/genética , Ocludina/metabolismo , Ratos , Ratos Zucker , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
16.
J Cachexia Sarcopenia Muscle ; 10(3): 696-709, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30927336

RESUMO

BACKGROUND: Sarcopenia is the loss of muscle mass/function that occurs during the aging process. The links between mechanistic target of rapamycin (mTOR) activity and muscle development are largely documented, but the role of its downstream targets in the development of sarcopenia is poorly understood. Eukaryotic initiation factor 4E-binding proteins (4E-BPs) are targets of mTOR that repress mRNA translation initiation and are involved in the control of several physiological processes. However, their role in skeletal muscle is still poorly understood. The goal of this study was to assess how loss of 4E-BP1 and 4E-BP2 expression impacts skeletal muscle function and homeostasis in aged mice and to characterize the associated metabolic changes by metabolomic and lipidomic profiling. METHODS: Twenty-four-month-old wild-type and whole body 4E-BP1/4E-BP2 double knockout (DKO) mice were used to measure muscle mass and function. Protein homeostasis was measured ex vivo in extensor digitorum longus by incorporation of l-[U-14 C]phenylalanine, and metabolomic and lipidomic profiling of skeletal muscle was performed by Metabolon, Inc. RESULTS: The 4E-BP1/2 DKO mice exhibited an increase in muscle mass that was associated with increased grip strength (P < 0.05). Protein synthesis was higher under both basal (+102%, P < 0.05) and stimulated conditions (+65%, P < 0.05) in DKO skeletal muscle. Metabolomic and complex lipid analysis of skeletal muscle revealed robust differences pertaining to amino acid homeostasis, carbohydrate abundance, and certain aspects of lipid metabolism. In particular, levels of most free amino acids were lower within the 4E-BP1/2 DKO muscle. Interestingly, although glucose levels were unchanged, differences were observed in the isobaric compound maltitol/lactitol (33-fold increase, P < 0.01) and in several additional carbohydrate compounds. 4E-BP1/2 depletion also resulted in accumulation of medium-chain acylcarnitines and a 20% lower C2/C0 acylcarnitine ratio (P < 0.01) indicative of reduced ß-oxidation. CONCLUSIONS: Taken together, these findings demonstrate that deletion of 4E-BPs is associated with perturbed energy metabolism in skeletal muscle and could have beneficial effects on skeletal muscle mass and function in aging mice. They also identify 4E-BPs as potential targets for the treatment of sarcopenia.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Envelhecimento/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fatores de Iniciação em Eucariotos/metabolismo , Biossíntese de Proteínas/genética , Sarcopenia/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Aminoácidos/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Modelos Animais de Doenças , Metabolismo Energético/genética , Fatores de Iniciação em Eucariotos/genética , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Metabolômica , Camundongos , Camundongos Knockout , Músculo Esquelético/patologia , Proteostase/genética , Sarcopenia/genética , Sarcopenia/terapia , Transdução de Sinais/genética
17.
J Cachexia Sarcopenia Muscle ; 10(2): 323-337, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30697967

RESUMO

BACKGROUND: Loss of muscle mass worsens many diseases such as cancer and renal failure, contributes to the frailty syndrome, and is associated with an increased risk of death. Studies conducted on animal models have revealed the preponderant role of muscle proteolysis and in particular the activation of the ubiquitin proteasome system (UPS). Studies conducted in humans remain scarce, especially within renal deficiency. Whether a shared atrophying programme exists independently of the nature of the disease remains to be established. The aim of this work was to identify common modifications at the transcriptomic level or the proteomic level in atrophying skeletal muscles from cancer and renal failure patients. METHODS: Muscle biopsies were performed during scheduled interventions in early-stage (no treatment and no detectable muscle loss) lung cancer (LC), chronic haemodialysis (HD), or healthy (CT) patients (n = 7 per group; 86% male; 69.6 ± 11.4, 67.9 ± 8.6, and 70.2 ± 7.9 years P > 0.9 for the CT, LC, and HD groups, respectively). Gene expression of members of the UPS, autophagy, and apoptotic systems was measured by quantitative real-time PCR. A global analysis of the soluble muscle proteome was conducted by shotgun proteomics for investigating the processes altered. RESULTS: We found an increased expression of several UPS and autophagy-related enzymes in both LC and HD patients. The E3 ligases MuRF1 (+56 to 78%, P < 0.01), MAFbx (+68 to 84%, P = 0.02), Hdm2 (+37 to 59%, P = 0.02), and MUSA1/Fbxo30 (+47 to 106%, P = 0.01) and the autophagy-related genes CTPL (+33 to 47%, P = 0.03) and SQSTM1 (+47 to 137%, P < 0.01) were overexpressed. Mass spectrometry identified >1700 proteins, and principal component analysis revealed three differential proteomes that matched to the three groups of patients. Orthogonal partial least square discriminant analysis created a model, which distinguished the muscles of diseased patients (LC or HD) from those of CT subjects. Proteins that most contributed to the model were selected. Functional analysis revealed up to 238 proteins belonging to nine metabolic processes (inflammatory response, proteolysis, cytoskeleton organization, glucose metabolism, muscle contraction, oxidant detoxification, energy metabolism, fatty acid metabolism, and extracellular matrix) involved in and/or altered by the atrophying programme in both LC and HD patients. This was confirmed by a co-expression network analysis. CONCLUSIONS: We were able to identify highly similar modifications of several metabolic pathways in patients exhibiting diseases with different aetiologies (early-stage LC vs. long-term renal failure). This strongly suggests that a common atrophying programme exists independently of the disease in human.


Assuntos
Falência Renal Crônica/complicações , Neoplasias Pulmonares/complicações , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Idoso , Autofagia , Biomarcadores , Biópsia , Biologia Computacional/métodos , Metabolismo Energético , Feminino , Hemólise , Humanos , Falência Renal Crônica/diagnóstico , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/diagnóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Proteômica , Transdução de Sinais
18.
Cells ; 8(1)2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634469

RESUMO

Crohn's disease is characterized by abnormal ileal colonization by adherent-invasive E. coli (AIEC) and expansion of mesenteric adipose tissue. This study assessed the preventive effect of spontaneous physical activity (PA) on the gut-adipose tissue in a mouse model that mimics Crohn's disease susceptibility. Thirty-five CEABAC10 male mice performed spontaneous PA (wheel group; n = 24) or not (controls; n = 11) for 12 weeks. At week 12, mice were orally challenged with the AIEC LF82 strain for 6 days. Body composition, glycaemic control, intestinal permeability, gut microbiota composition, and fecal short-chain fatty acids were assessed in both groups. Animals were fed a high fat/high sugar diet throughout the study. After exposure to AIEC, mesenteric adipose tissue weight was lower in the wheel group. Tight junction proteins expression increased with spontaneous PA, whereas systemic lipopolysaccharides were negatively correlated with the covered distance. Bifidobacterium and Lactobacillus decreased in controls, whereas Oscillospira and Ruminococcus increased in the wheel group. Fecal propionate and butyrate were also higher in the wheel group. In conclusion, spontaneous physical activity promotes healthy gut microbiota composition changes and increases short-chain fatty acids in CEABAC10 mice fed a Western diet and exposed to AIEC to mimic Crohn's disease.


Assuntos
Tecido Adiposo/metabolismo , Doença de Crohn/prevenção & controle , Intestinos/microbiologia , Esforço Físico , Animais , Aderência Bacteriana , Doença de Crohn/microbiologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Escherichia coli/patogenicidade , Infecções por Escherichia coli/metabolismo , Ácidos Graxos Voláteis/metabolismo , Feminino , Microbioma Gastrointestinal , Glucose/metabolismo , Masculino , Camundongos , Camundongos Transgênicos
19.
Magnes Res ; 32(3): 72-82, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32162608

RESUMO

Magnesium (Mg2+) is critical for a number of biological processes and 25% body Mg2+ is located in the skeletal muscle. Mg2+ transport and homeostasis systems (MgTHs) regulate intracellular Mg2+ concentration and muscle MgTHs are thus related to whole body Mg2+ homeostasis. Nonetheless, few studies have investigated the regulation of muscle MgTHs under (patho)physiological conditions. Herein, we assessed the relationship between the expression of MgTHs genes (Trpm6, Trpm7, Magt1, Mrs2, Cnnm1-4, Slc41a1-3) and relevant pathways in human sarcopenia, which is one of the most dramatic physiologic changes affecting the human body. Transcriptomic data were compared between young adult (YO, 22 y, n = 11) and old (EL, 73 y, n = 13) men from the PROOF cohort. MgTH mRNA levels did not change with aging, with the exception of a slight decrease for Slc41a3. Nevertheless, interindividual variations of mRNA levels revealed strong correlations between MgTHs in the YO group, while few were maintained in the EL muscle. Moreover, in the YO muscle, different clusters of MgTH mRNAs strongly correlated with divers physiological (BMI, blood pressure) and muscle characteristics (intramyocellular droplets, capillarization); however, most correlations changed or disappeared in the EL muscle. Further investigations of the whole transcriptome identified several sets of mRNAs correlated with defined MgTHs. There again was a sharp difference between YO and EL muscles, as the number of mRNAs correlated with MgTHs strongly decreased with aging. Gene ontology analyses of these sets of correlated mRNAs revealed 6 biological processes common to YO and EL, 3 specific to the YO (RNA processing, translation, respiration), and 2 (regulation of catabolic process, Wnt signaling) to the EL muscle. Overall, these observations lead to questions about potential resilience to muscle Mg2+ homeostasis in the elderly.


Assuntos
Homeostase/genética , Magnésio/metabolismo , Músculo Esquelético/metabolismo , Transcriptoma , Adulto , Idoso , Estudos de Coortes , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Adulto Jovem
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