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1.
Traffic ; 25(1): e12926, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38084815

RESUMO

In neurons, fast axonal transport (FAT) of vesicles occurs over long distances and requires constant and local energy supply for molecular motors in the form of adenosine triphosphate (ATP). FAT is independent of mitochondrial metabolism. Indeed, the glycolytic machinery is present on vesicles and locally produces ATP, as well as nicotinamide adenine dinucleotide bonded with hydrogen (NADH) and pyruvate, using glucose as a substrate. It remains unclear whether pyruvate is transferred to mitochondria from the vesicles as well as how NADH is recycled into NAD+ on vesicles for continuous glycolysis activity. The optimization of a glycolytic activity test for subcellular compartments allowed the evaluation of the kinetics of vesicular glycolysis in the brain. This revealed that glycolysis is more efficient on vesicles than in the cytosol. We also found that lactate dehydrogenase (LDH) enzymatic activity is required for effective vesicular ATP production. Indeed, inhibition of LDH or the forced degradation of pyruvate inhibited ATP production from axonal vesicles. We found LDHA rather than the B isoform to be enriched on axonal vesicles suggesting a preferential transformation of pyruvate to lactate and a concomitant recycling of NADH into NAD+ on vesicles. Finally, we found that LDHA inhibition dramatically reduces the FAT of both dense-core vesicles and synaptic vesicle precursors in a reconstituted cortico-striatal circuit on-a-chip. Together, this shows that aerobic glycolysis is required to supply energy for vesicular transport in neurons, similar to the Warburg effect.


Assuntos
Glicólise , NAD , NAD/metabolismo , Glicólise/fisiologia , Axônios/metabolismo , Trifosfato de Adenosina/metabolismo , Piruvatos/metabolismo
2.
Antioxidants (Basel) ; 11(8)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-36009181

RESUMO

RATIONALE: Intermittent hypoxia (IH) is one of the main features of sleep-disordered breathing (SDB). Recent findings indicate that hypoxia inducible factor-1 (HIF-1) promotes cardiomyocytes apoptosis during chronic IH, but the mechanisms involved remain to be elucidated. Here, we hypothesize that IH-induced ER stress is associated with mitochondria-associated ER membrane (MAM) alteration and mitochondrial dysfunction, through HIF-1 activation. METHODS: Right atrial appendage biopsies from patients with and without SDB were used to determine HIF-1α, Grp78 and CHOP expressions. Wild-type and HIF-1α+/- mice were exposed to normoxia (N) or IH (21-5% O2, 60 cycles/h, 8 h/day) for 21 days. Expressions of HIF-1α, Grp78 and CHOP, and apoptosis, were measured by Western blot and immunochemistry. In isolated cardiomyocytes, we examined structural integrity of MAM by proximity ligation assay and their function by measuring ER-to-mitochondria Ca2+ transfer by confocal microscopy. Finally, we measured mitochondrial respiration using oxygraphy and calcium retention capacity (CRC) by spectrofluorometry. MAM structure was also investigated in H9C2 cells incubated with 1 mM CoCl2, a potent HIF-1α inducer. RESULTS: In human atrial biopsies and mice, IH induced HIF-1 activation, ER stress and apoptosis. IH disrupted MAM, altered Ca2+ homeostasis, mitochondrial respiration and CRC. Importantly, IH had no effect in HIF-1α+/- mice. Similar to what observed under IH, HIF-1α overexpression was associated with MAM alteration in H9C2. CONCLUSION: IH-induced ER stress, MAM alterations and mitochondrial dysfunction were mediated by HIF-1; all these intermediate mechanisms ultimately inducing cardiomyocyte apoptosis. This suggests that HIF-1 modulation might limit the deleterious cardiac effects of SDB.

3.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1867(12): 159223, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35987325

RESUMO

The perinatal exposome can modify offspring metabolism and health later in life. Within this concept, maternal exercise during gestation has been reported modifying offspring glucose sensing and homeostasis, while the impact of such exercise during lactation is little-known. We thus aimed at evaluating short- and long-term effects of it on offspring pancreatic function, assuming a link with changes in breast milk composition. Fifteen-week-old primiparous female Wistar rats exercised during lactation at a constant submaximal intensity (TR) or remained sedentary (CT). Male offspring were studied at weaning and at 7 months of age for growth, pancreas weight, glycemia and insulin responses. Milk protein content was determined by the bicinchoninic acid assay (BCA colorimetric method), and lipid content and fatty acid composition by gas chromatography. Mature milk from TR rats contained significantly less saturated (-7 %) and more monounsaturated (+18 %) and polyunsaturated (PUFA +12 %) fatty acids compared to CT rats, with no difference in total lipid and protein concentrations. In offspring from TR vs CT mothers, fasting glycemia was lower, pancreas weight was higher with a lower insulin content (-37 %) at weaning. Such outcomes were correlated with milk PUFA levels and indices of desaturase or elongase activities. These effects were no longer present at 7 months, whereas a more efficient muscle insulin sensitivity was observed. Maternal training during lactation led to a specific milk phenotype that was associated with a short-term impact on glucose homeostasis and pancreatic function of the male offspring.


Assuntos
Ácidos Graxos , Leite , Condicionamento Físico Animal , Animais , Glicemia/metabolismo , Ácidos Graxos Dessaturases , Elongases de Ácidos Graxos , Ácidos Graxos/análise , Feminino , Homeostase , Insulina/metabolismo , Lactação , Masculino , Leite/química , Proteínas do Leite/análise , Gravidez , Ratos , Ratos Wistar
4.
J. physiol. biochem ; 78(2): 501-516, May. 2022.
Artigo em Inglês | IBECS | ID: ibc-215977

RESUMO

The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. (AU)


Assuntos
Animais , Ratos , Magnésio/metabolismo , Magnésio/farmacologia , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo
5.
Nutrients ; 14(3)2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35276859

RESUMO

It remains unclear whether sickle cell trait (SCT) should be considered a risk factor during intense physical activity. By triggering the polymerization-sickling-vaso-occlusion cascade, lactate accumulation-associated acidosis in response to high-intensity exercise is believed to be one of the causes of complications. However, our understanding of lactate metabolism in response to high-intensity exercise in SCT carriers is incomplete. Thirty male SCT carriers (n = 15) and healthy subjects (n = 15) with and without α-thalassemia performed a 2-min high-intensity exercise. Blood and muscle lactate concentrations were measured at exercise completion. Time courses of blood lactate and glucose concentrations were followed during the subsequent recovery. Additional biochemical analyses were performed on biopsies of the vastus lateralis muscle. SCT was associated with lower blood and muscle lactate concentrations in response to the short high-intensity exercise. Compared to controls, the muscle content among SCT carriers of lactate transporter MCT4 and ß2-adrenergic receptor were higher and lower, respectively. During recovery, the lactate removal ability was higher in SCT carriers. In the present study, no effect of α-thalassemia was observed. The lower blood and muscle lactate accumulations in SCT carriers may, to some extent, act as protective mechanisms: (i) against exercise-related acidosis and subsequent sickling, that may explain the relatively rare complications observed in exercising SCT carriers; and (ii) against the deleterious effects of intracellular lactate and associated acidosis on muscle function, that might explain the elevated presence of SCT carriers among the best sprinters.


Assuntos
Traço Falciforme , Exercício Físico/fisiologia , Teste de Esforço , Humanos , Ácido Láctico , Masculino , Músculos , Traço Falciforme/genética
6.
J Physiol Biochem ; 78(2): 501-516, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34292519

RESUMO

The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. Taken together, these results suggest that a chronic low-dose L-lactate intake has a beneficial health effect on some skeletal muscles and the myocardium through the activation of the NHE1/NCX1 axis, a decrease in cellular calcium and an increase in cellular magnesium. The treatment can be beneficial for the health of young rodents in relation to chronic oxidative stress-related diseases.


Assuntos
Cálcio , Magnésio , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Lactatos/metabolismo , Magnésio/metabolismo , Magnésio/farmacologia , Masculino , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Wistar , Sódio/metabolismo , Água
7.
Front Cell Dev Biol ; 9: 731015, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733845

RESUMO

AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis under conditions of energy stress. Though heart is one of the most energy requiring organs and depends on a perfect match of energy supply with high and fluctuating energy demand to maintain its contractile performance, the role of AMPK in this organ is still not entirely clear, in particular in a non-pathological setting. In this work, we characterized cardiomyocyte-specific, inducible AMPKα1 and α2 knockout mice (KO), where KO was induced at the age of 8 weeks, and assessed their phenotype under physiological conditions. In the heart of KO mice, both AMPKα isoforms were strongly reduced and thus deleted in a large part of cardiomyocytes already 2 weeks after tamoxifen administration, persisting during the entire study period. AMPK KO had no effect on heart function at baseline, but alterations were observed under increased workload induced by dobutamine stress, consistent with lower endurance exercise capacity observed in AMPK KO mice. AMPKα deletion also induced a decrease in basal metabolic rate (oxygen uptake, energy expenditure) together with a trend to lower locomotor activity of AMPK KO mice 12 months after tamoxifen administration. Loss of AMPK resulted in multiple alterations of cardiac mitochondria: reduced respiration with complex I substrates as measured in isolated mitochondria, reduced activity of complexes I and IV, and a shift in mitochondrial cristae morphology from lamellar to mixed lamellar-tubular. A strong tendency to diminished ATP and glycogen level was observed in older animals, 1 year after tamoxifen administration. Our study suggests important roles of cardiac AMPK at increased cardiac workload, potentially limiting exercise performance. This is at least partially due to impaired mitochondrial function and bioenergetics which degrades with age.

9.
Int J Sports Med ; 41(13): 936-943, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32643774

RESUMO

This study aimed to test if the non-oxidative energy supply (estimated by the accumulated oxygen deficit) is associated with an index of muscle lactate accumulation during exercise, muscle monocarboxylate transporter content and the lactate removal ability during recovery in well-trained rowers. Seventeen rowers completed a 3-min all-out exercise on rowing ergometer to estimate the accumulated oxygen deficit. Blood lactate samples were collected during the subsequent passive recovery to assess individual blood lactate curves, which were fitted to the bi-exponential time function: La(t)= [La](0)+A1·(1-e-γ 1 t)+A2·(1-e-γ 2 t), where the velocity constants γ1 and γ2 (min-1) denote the lactate exchange and removal abilities during recovery, respectively. The accumulated oxygen deficit was correlated with the net amount of lactate released from the previously active muscles (r =0.58, P<0.05), the monocarboxylate transporters MCT1 and MCT4 (r=0.63, P<0.05) and γ2 (r=0.55, P<0.05). γ2 and the lactate release rate at exercise completion were negatively correlated with citrate synthase activity. These findings suggest that the capacity to supply non-oxidative energy during supramaximal rowing exercise is associated with muscle lactate accumulation and transport, as well as lactate removal ability.


Assuntos
Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Simportadores/metabolismo , Esportes Aquáticos/fisiologia , Metabolismo Energético , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/sangue , Condicionamento Físico Humano/fisiologia , Adulto Jovem
10.
J Exp Biol ; 222(Pt 10)2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31019067

RESUMO

It is now well established that the intrauterine environment is of major importance for offspring health during later life. Endurance training during pregnancy is associated with positive metabolic adjustments and beneficial effects on the balance between pro-oxidants and antioxidants (redox state) in the offspring. Our hypothesis was that these changes could rely on mitochondrial adaptations in the offspring due to modifications of the fetal environment induced by maternal endurance training. Therefore, we compared the liver and skeletal muscle mitochondrial function and the redox status of young rats whose mothers underwent moderate endurance training (treadmill running) before and during gestation (T) with those of young rats from untrained mothers (C). Our results show a significant reduction in the spontaneous H2O2 release by liver and muscle mitochondria in the T versus C offspring (P<0.05). These changes were accompanied by alterations in oxygen consumption. Moreover, the percentage of short-chain fatty acids increased significantly in liver mitochondria from T offspring. This may lead to improvements in the fluidity and the flexibility of the membrane. In plasma, glutathione peroxidase activity and protein oxidation were significantly higher in T offspring than in C offspring (P<0.05). Such changes in plasma could represent an adaptive signal transmitted from mothers to their offspring. We thus demonstrated for the first time, to our knowledge, that it is possible to act on bioenergetic function including alterations of mitochondrial function in offspring by modifying maternal physical activity before and during pregnancy. These changes could be crucial for the future health of the offspring.


Assuntos
Fígado/metabolismo , Mitocôndrias/metabolismo , Mães , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Animais , Feminino , Membro Posterior/fisiologia , Masculino , Mitocôndrias Hepáticas/metabolismo , Gravidez , Ratos , Ratos Wistar
11.
Int J Mol Sci ; 19(8)2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30061518

RESUMO

Pulmonary hypertension is a co-morbidity, which strongly participates in morbi-mortality in patients with chronic obstructive pulmonary disease (COPD). Recent findings showed that bromodomain-containing proteins, in charge of reading histone acetylation, could be involved in pulmonary arterial hypertension. Our aim was to study the effect of I-BET151, an inhibitor of bromodomain and extra-terminal domain (BET), on the right ventricle hypertrophy and pulmonary hypertension, induced by a combination of chronic hypoxia and pulmonary inflammation, as the two main stimuli encountered in COPD. Adult Wistar male rats, exposed to chronic hypoxia plus pulmonary inflammation (CHPI), showed a significant right ventricle hypertrophy (+57%, p < 0.001), an increase in systolic pressure (+46%, p < 0.001) and in contraction speed (+36%, p < 0.001), when compared to control animals. I-BET151 treated animals (CHPI-iB) showed restored hemodynamic parameters to levels similar to control animals, despite chronic hypoxia plus exposure to pulmonary inflammation. They displayed lower right ventricle hypertrophy and hematocrit compared to the CHPI group (respectively -16%, p < 0.001; and -9%, p < 0.05). Our descriptive study shows a valuable effect of the inhibition of bromodomain and extra-terminal domain proteins on hemodynamic parameters, despite the presence of chronic hypoxia and pulmonary inflammation. This suggests that such inhibition could be of potential interest for COPD patients with pulmonary hypertension. Further studies are needed to unravel the underlying mechanisms involved and the net benefits of inhibiting adaptations to chronic hypoxia.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertrofia Ventricular Direita/tratamento farmacológico , Hipertrofia Ventricular Direita/etiologia , Hipóxia/complicações , Pneumonia/complicações , Fatores de Transcrição/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/patologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipóxia/patologia , Hipóxia/fisiopatologia , Masculino , Pneumonia/patologia , Pneumonia/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ratos Wistar
12.
J Bioenerg Biomembr ; 50(5): 367-377, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30136168

RESUMO

There is substantial evidence that Reactive Oxygen Species (ROS) play a major part in cell functioning. Although their harmfulness through oxidative stress is well documented, their role in signaling and sensing as an oxidative signal still needs to be investigated. In most cells, the mitochondrial Electron Transport Chain (ETC) is the primary source of ROS. The production of ROS by reverse electron transfer through complex I has been demonstrated both in an experimental context but also in many pathophysiological situations. Therefore, understanding the mechanisms that regulate this ROS production is of great interest to control its harmful effects. We used nigericin, Pi and valinomycin as tools to modulate the pH gradient (∆pH) and the membrane potential (∆Ψ) of the protonmotive force (∆p) in liver and muscle mitochondria to accurately determine how these parameters control the ROS production. We show that a high ∆Ψ is the "sine qua none" condition for ROS production from the reverse electron transfer (RET) through the complex I. However, a high ∆Ψ is not the only condition governing ROS production. Indeed, using tools that modulate the mitochondrial NADH level, we also demonstrate that ROS production is directly related to the mitochondrial redox potential when the membrane potential is almost stable.


Assuntos
Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias Cardíacas/metabolismo , NAD/metabolismo , Animais , Humanos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio
13.
Mol Cell ; 69(4): 594-609.e8, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29452639

RESUMO

Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) in vitro and in vivo, impinging on respiratory complex I activity and enhancing mitochondrial ROS production. Recruitment of MDM2 to mitochondria increases during oxidative stress and hypoxia. Accordingly, mice lacking MDM2 in skeletal muscles exhibit higher MT-ND6 levels, enhanced complex I activity, and increased muscular endurance in mild hypoxic conditions. Furthermore, increased mitochondrial MDM2 levels enhance the migratory and invasive properties of cancer cells. Collectively, these data uncover a previously unsuspected function of the MDM2 oncoprotein in mitochondria that play critical roles in skeletal muscle physiology and may contribute to tumor progression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica/patologia , Complexo I de Transporte de Elétrons/metabolismo , Regulação Neoplásica da Expressão Gênica , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Complexo I de Transporte de Elétrons/genética , Genoma Mitocondrial , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Invasividade Neoplásica , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-mdm2/genética , Transdução de Sinais , Transcrição Gênica , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Physiol ; 595(23): 7049-7062, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28971475

RESUMO

KEY POINTS: Maternal training during gestation enhances offspring body composition and energy substrates handling in early adulthood. Offspring nutrition also plays a role as some beneficial effects of maternal training during gestation disappear after consumption of a high-fat diet. ABSTRACT: Maternal exercise during gestation has been reported to modify offspring metabolism and health. Whether these effects are exacerbated when offspring are receiving a high-fat diet remains unclear. Our purpose was to evaluate the effect of maternal exercise before and during gestation on the offspring fed a high-fat/high-sucrose diet (HF) by assessing its body composition, pancreatic function and energy substrates handling by two major glucose-utilizing tissues: liver and muscle. Fifteen-week-old nulliparous female Wistar rats exercised 4 weeks before as well as during gestation at a constant submaximal intensity (TR) or remained sedentary (CT). At weaning, pups from each group were fed either a standard diet (TRCD or CTCD) or a high-fat/high-sucrose diet (TRHF or CTHF) for 10 weeks. Offspring from TR dams gained less weight compared to those from CT dams. Selected fat depots were larger with the HF diet compared to control diet (CD) but significantly smaller in TRHF compared to CTHF. Surprisingly, the insulin secretion index was higher in islets from HF offspring compared to CD. TR offspring showed a higher muscle insulin sensitivity estimated by the ratio of phosphorylated protein kinase B to total protein kinase B compared with CT offspring (+48%, P < 0.05). With CD, permeabilized isolated muscle fibres from TR rats displayed a lower apparent affinity constant (Km ) for pyruvate and palmitoyl coenzyme A as substrates compared to the CT group (-46% and -58%, respectively, P < 0.05). These results suggest that maternal exercise has positive effects on young adult offspring body composition and on muscle carbohydrate and lipid metabolism depending on the nutritional status.


Assuntos
Composição Corporal , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Metabolismo Energético , Condicionamento Físico Animal , Animais , Células Cultivadas , Sacarose Alimentar/administração & dosagem , Feminino , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Metabolismo dos Lipídeos , Masculino , Músculo Esquelético/metabolismo , Gravidez , Ratos , Ratos Wistar
15.
Sci Rep ; 7(1): 12133, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28935884

RESUMO

Some of the Chronic Obstructive Pulmonary Disease (COPD) patients engaged in exercise-based muscle rehabilitation programs are unresponsive. To unravel the respective role of chronic hypoxia and pulmonary inflammation on soleus muscle hypertrophic capacities, we challenged male Wistar rats to repeated lipopolysaccharide instillations, associated or not with a chronic hypoxia exposure. Muscle hypertrophy was initiated by bilateral ablation of soleus agonists 1 week before sacrifice. To understand the role played by the histone acetylation, we also treated our animals with an inhibitor of bromodomains and extra terminal proteins (I-BET) during the week after surgery. Pulmonary inflammation totally inhibited this hypertrophy response under both normoxic and hypoxic conditions (26% lower than control surgery, p < 0.05), consistent with the S6K1 and myogenin measurements. Changes in histone acetylation and class IIa histone deacetylases expression, following pulmonary inflammation, suggested a putative role for histone acetylation signaling in the altered hypertrophy response. The I-BET drug restored the hypertrophy response suggesting that the non-response of muscle to a hypertrophic stimulus could be modulated by epigenetic mechanisms, including histone-acetylation dependant pathways. Drugs targeting such epigenetic mechanisms may open therapeutic perspectives for COPD patients with systemic inflammation who are unresponsive to rehabilitation.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Hipertrofia/complicações , Hipóxia/complicações , Músculo Esquelético/patologia , Doenças Musculares/complicações , Pneumonia/complicações , Doença Pulmonar Obstrutiva Crônica/complicações , Acetilação/efeitos dos fármacos , Animais , Histonas/metabolismo , Humanos , Hipertrofia/tratamento farmacológico , Hipertrofia/metabolismo , Hipertrofia/patologia , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Hipóxia/patologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Doenças Musculares/tratamento farmacológico , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/patologia , Domínios Proteicos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Ratos Wistar
16.
J Physiol ; 595(11): 3361-3376, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28251652

RESUMO

KEY POINTS: Silent mating type information regulation 2 homologue 1 (SIRT1) activity and content increased significantly in overload-induced hypertrophy. SIRT1-mediated signalling through Akt, the endothelial nitric oxide synthase mediated pathway, regulates anabolic process in the hypertrophy of skeletal muscle. The regulation of catabolic signalling via forkhead box O 1 and protein ubiquitination is SIRT1 dependent. Overload-induced changes in microRNA levels regulate SIRT1 and insulin-like growth factor 1 signalling. ABSTRACT: Significant skeletal muscle mass guarantees functional wellbeing and is important for high level performance in many sports. Although the molecular mechanism for skeletal muscle hypertrophy has been well studied, it still is not completely understood. In the present study, we used a functional overload model to induce plantaris muscle hypertrophy by surgically removing the soleus and gastrocnemius muscles in rats. Two weeks of muscle ablation resulted in a 40% increase in muscle mass, which was associated with a significant increase in silent mating type information regulation 2 homologue 1 (SIRT1) content and activity (P < 0.001). SIRT1-regulated Akt, endothelial nitric oxide synthase and GLUT4 levels were also induced in hypertrophied muscles, and SIRT1 levels correlated with muscle mass, paired box protein 7 (Pax7), proliferating cell nuclear antigen (PCNA) and nicotinamide phosphoribosyltransferase (Nampt) levels. Alternatively, decreased forkhead box O 1 (FOXO1) and increased K48 polyubiquitination also suggest that SIRT1 could be involved in the catabolic process of hypertrophy. Furthermore, increased levels of K63 and muscle RING finger 2 (MuRF2) protein could also be important enhancers of muscle mass. We report here that the levels of miR1 and miR133a decrease in hypertrophy and negatively correlate with muscle mass, SIRT1 and Nampt levels. Our results reveal a strong correlation between SIRT1 levels and activity, SIRT1-regulated pathways and overload-induced hypertrophy. These findings, along with the well-known regulatory roles that SIRT1 plays in modulating both anabolic and catabolic pathways, allow us to propose the hypothesis that SIRT1 may actually play a crucial causal role in overload-induced hypertrophy of skeletal muscle. This hypothesis will now require rigorous direct and functional testing.


Assuntos
Contração Muscular , Músculo Esquelético/patologia , Sirtuína 1/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Hipertrofia , Masculino , MicroRNAs/genética , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Sirtuína 1/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
17.
Sci Rep ; 7: 43663, 2017 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-28255159

RESUMO

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21-5% FiO2, 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy.


Assuntos
Autofagia , Hipóxia/metabolismo , Resistência à Insulina , Condicionamento Físico Animal , Tecido Adiposo/metabolismo , Animais , Biomarcadores , Peso Corporal , Ingestão de Alimentos , Hematócrito , Insulina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Transdução de Sinais , Apneia Obstrutiva do Sono/complicações
18.
Clin Sci (Lond) ; 131(8): 775-790, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28250083

RESUMO

Background: Exercise and citrulline (CIT) are both regulators of muscle protein metabolism. However, the combination of both has been under-studied yet may have synergistic effects on muscle metabolism and performance. Methods: Three-month-old healthy male rats were randomly assigned to be fed ad libitum for 4 weeks with either a citrulline-enriched diet (1 g·kg-1·day-1) (CIT) or an isonitrogenous standard diet (by addition of nonessential amino acid) (Ctrl) and trained (running on treadmill 5 days·week-1) (ex) or not. Maximal endurance activity and body composition were assessed, and muscle protein metabolism (protein synthesis, proteomic approach) and energy metabolism [energy expenditure, mitochondrial metabolism] were explored. Results: Body composition was affected by exercise but not by CIT supplementation. Endurance training was associated with a higher maximal endurance capacity than sedentary groups (P<0.001), and running time was 14% higher in the CITex group than the Ctrlex group (139±4 min versus 122±6 min, P<0.05). Both endurance training and CIT supplementation alone increased muscle protein synthesis (by +27% and +33%, respectively, versus Ctrl, P<0.05) with an additive effect (+48% versus Ctrl, P<0.05). Mitochondrial metabolism was modulated by exercise but not directly by CIT supplementation. However, the proteomic approach demonstrated that CIT supplementation was able to affect energy metabolism, probably due to activation of pathways generating acetyl-CoA. Conclusion: CIT supplementation and endurance training in healthy male rats modulates both muscle protein and energy metabolisms, with synergic effects on an array of parameters, including performance and protein synthesis.


Assuntos
Citrulina/farmacologia , Suplementos Nutricionais , Metabolismo Energético/fisiologia , Proteínas Musculares/metabolismo , Condicionamento Físico Animal , Animais , Composição Corporal , Citrulina/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Masculino , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Resistência Física/efeitos dos fármacos , Resistência Física/fisiologia , Proteômica/métodos , Distribuição Aleatória , Ratos Wistar
19.
Front Physiol ; 7: 223, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27375499

RESUMO

The purpose of this study was to test if the lactate exchange (γ1) and removal (γ2) abilities during recovery following short all-out supramaximal exercise correlate with the muscle content of MCT1 and MCT4, the two isoforms of the monocarboxylate transporters family involved in lactate and H(+) co-transport in skeletal muscle. Eighteen lightweight rowers completed a 3-min all-out exercise on rowing ergometer. Blood lactate samples were collected during the subsequent passive recovery to assess an individual blood lactate curve (IBLC). IBLC were fitted to the bi-exponential time function: La(t) = [La](0) + A1(1 - [Formula: see text]) + A2(1 - [Formula: see text]) where [La](0) is the blood lactate concentration at exercise completion and the velocity constants γ1 and γ2 denote the lactate exchange and removal abilities, respectively. An application of the bi-compartmental model of lactate distribution space allowed estimation of the lactate removal rate at exercise completion [LRR(0)]. Biopsy of the right vastus lateralis was taken at rest to measure muscle MCT1 and MCT4 content. Fiber type distribution, activity of key enzymes and capillary density (CD) were also assessed. γ1 was correlated with [La](0) (r = -0.54, P < 0.05) but not with MCT1, MCT4 or CD. γ2 and LRR(0) were correlated with MCT4 (r = 0.63, P < 0.01 and r = 0.73, P < 0.001, respectively) but not with MCT1 or cytochrome c oxidase activity. These findings suggest that the lactate exchange ability is highly dependent on the milieu so that the importance of the muscle MCT1 and MCT4 content in γ1 was hidden in the present study. Our results also suggest that during recovery following all-out supramaximal exercise in well-trained rowers, MCT4 might play a significant role in the distribution and delivery of lactate for its subsequent removal.

20.
Am J Physiol Endocrinol Metab ; 311(2): E508-18, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27382034

RESUMO

Only a few studies have explored the effects of maternal exercise during gestation on adult offspring metabolism. We set out to test whether maternal controlled submaximal exercise maintained troughout all gestational periods induces persistant metabolic changes in the offspring. We used a model of 15-wk-old nulliparous female Wistar rats that exercised (trained group) before and during gestation at a submaximal intensity or remained sedentary (control group). At weaning, male offspring from trained dams showed reduced basal glycemia (119.7 ± 2.4 vs. 130.5 ± 4.1 mg/dl, P < 0.05), pancreas relative weight (3.96 ± 0.18 vs. 4.54 ± 0.14 g/kg body wt, P < 0.05), and islet mean area (22,822 ± 4,036 vs. 44,669 ± 6,761 µm(2), P < 0.05) compared with pups from control dams. Additionally, they had better insulin secretory capacity when stimulated by 2.8 mM glucose + 20 mM arginine compared with offspring from control dams (+96%, P < 0.05). At 7 mo of age, offspring from trained mothers displayed altered glucose tolerance (AUC = 15,285 ± 527 vs. 11,898 ± 988 mg·dl(-1)·120 min, P < 0.05) and decreased muscle insulin sensitivity estimated by the phosphorylated PKB/total PKB ratio (-32%, P < 0.05) and tended to have a reduced islet insulin secretory capacity compared with rats from control dams. These results suggest that submaximal maternal exercise modifies short-term male offspring pancreatic function and appears to have rather negative long-term consequences on sedentary adult offspring glucose handling.


Assuntos
Glicemia/metabolismo , Resistência à Insulina , Ilhotas Pancreáticas/patologia , Músculo Esquelético/metabolismo , Condicionamento Físico Animal , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Western Blotting , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Homeostase , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Masculino , Tamanho do Órgão , Pâncreas/patologia , Fosfoproteínas/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Desmame
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