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1.
Sci Rep ; 12(1): 15870, 2022 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-36151270

RESUMEN

Leucine (Leu) regulates protein synthesis and degradation via activation of mammalian target of rapamycin complex 1 (mTORC1). Glutamine (Gln) synergistically promotes mTORC1 activation with Leu via glutaminolysis and Leu absorption via an antiporter. However, Gln has also been shown to inhibit mTORC1 activity. To resolve this paradox, we aimed to elucidate the effects of Gln on Leu-mediated mTORC1 activation. We administered Leu, Gln, tryptophan, Leu + Gln, or Leu + tryptophan to mice after 24-h fasting. The mice were then administered puromycin to evaluate protein synthesis and the gastrocnemius muscle was harvested 30 min later. Phosphorylated eukaryotic initiation factor 4E-binding protein 1, 70-kDa ribosomal protein S6 kinase 1, and Unc-51 like kinase 1 levels were the highest in the Leu + Gln group and significantly increased compared with those in the control group; however, Gln alone did not increase the levels of phosphorylated proteins. No difference in glutamate dehydrogenase activity was observed between the groups. Leu concentrations in the gastrocnemius muscle were similar in the Leu-intake groups. Our study highlights a novel mechanism underlying the promotive effect of Gln on Leu-mediated mTORC1 activation, providing insights into the pathway through which amino acids regulate muscle protein metabolism.


Asunto(s)
Glutamina , Leucina , Diana Mecanicista del Complejo 1 de la Rapamicina , Aminoácidos/metabolismo , Animales , Antiportadores/metabolismo , Ingestión de Alimentos , Factor 4E Eucariótico de Iniciación/metabolismo , Glutamato Deshidrogenasa/metabolismo , Glutamina/administración & dosificación , Leucina/administración & dosificación , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Proteínas Musculares/metabolismo , Fosforilación , Puromicina , Triptófano/metabolismo
2.
Nutrients ; 12(1)2020 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-31963899

RESUMEN

Amino acids are components of proteins that also exist free-form in the body; their functions can be divided into (1) nutritional, (2) sensory, and (3) biological regulatory roles. The skeletal muscle, which is the largest organ in the human body, representing ~40% of the total body weight, plays important roles in exercise, energy expenditure, and glucose/amino acid usage-processes that are modulated by various amino acids and their metabolites. In this review, we address the metabolism and function of amino acids in the skeletal muscle. The expression of PGC1α, a transcriptional coactivator, is increased in the skeletal muscle during exercise. PGC1α activates branched-chain amino acid (BCAA) metabolism and is used for energy in the tricarboxylic acid (TCA) cycle. Leucine, a BCAA, and its metabolite, ß-hydroxy-ß-methylbutyrate (HMB), both activate mammalian target of rapamycin complex 1 (mTORC1) and increase protein synthesis, but the mechanisms of activation appear to be different. The metabolite of valine (another BCAA), ß-aminoisobutyric acid (BAIBA), is increased by exercise, is secreted by the skeletal muscle, and acts on other tissues, such as white adipose tissue, to increase energy expenditure. In addition, several amino acid-related molecules reportedly activate skeletal muscle function. Oral 5-aminolevulinic acid (ALA) supplementation can protect against mild hyperglycemia and help prevent type 2 diabetes. ß-alanine levels are decreased in the skeletal muscles of aged mice. ß-alanine supplementation increased the physical performance and improved the executive function induced by endurance exercise in middle-aged individuals. Further studies focusing on the effects of amino acids and their metabolites on skeletal muscle function will provide data essential for the production of food supplements for older adults, athletes, and individuals with metabolic diseases.


Asunto(s)
Aminoácidos/metabolismo , Proteínas en la Dieta/metabolismo , Metabolismo Energético , Desarrollo de Músculos , Músculo Esquelético/metabolismo , Aminoácidos/administración & dosificación , Animales , Proteínas en la Dieta/administración & dosificación , Suplementos Dietéticos , Metabolismo Energético/efectos de los fármacos , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Desarrollo de Músculos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Transducción de Señal
3.
Biochem Biophys Res Commun ; 481(3-4): 251-258, 2016 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-27816452

RESUMEN

The expression of the transcriptional coactivator PGC1α is increased in skeletal muscles during exercise. Previously, we showed that increased PGC1α leads to prolonged exercise performance (the duration for which running can be continued) and, at the same time, increases the expression of branched-chain amino acid (BCAA) metabolism-related enzymes and genes that are involved in supplying substrates for the TCA cycle. We recently created mice with PGC1α knockout specifically in the skeletal muscles (PGC1α KO mice), which show decreased mitochondrial content. In this study, global gene expression (microarray) analysis was performed in the skeletal muscles of PGC1α KO mice compared with that of wild-type control mice. As a result, decreased expression of genes involved in the TCA cycle, oxidative phosphorylation, and BCAA metabolism were observed. Compared with previously obtained microarray data on PGC1α-overexpressing transgenic mice, each gene showed the completely opposite direction of expression change. Bioinformatic analysis of the promoter region of genes with decreased expression in PGC1α KO mice predicted the involvement of several transcription factors, including a nuclear receptor, ERR, in their regulation. As PGC1α KO microarray data in this study show opposing findings to the PGC1α transgenic data, a loss-of-function experiment, as well as a gain-of-function experiment, revealed PGC1α's function in the oxidative energy metabolism of skeletal muscles.


Asunto(s)
Eliminación de Gen , Regulación de la Expresión Génica , Músculo Esquelético/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Transactivadores/metabolismo , Animales , Biología Computacional , Regulación hacia Abajo/genética , Masculino , Redes y Vías Metabólicas/genética , Ratones Noqueados , Mitocondrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxidación-Reducción , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/genética , Transactivadores/genética
4.
Biosci Biotechnol Biochem ; 80(2): 288-90, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26745679
5.
J Lipid Res ; 56(12): 2286-96, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26438561

RESUMEN

Exercise training influences phospholipid fatty acid composition in skeletal muscle and these changes are associated with physiological phenotypes; however, the molecular mechanism of this influence on compositional changes is poorly understood. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a nuclear receptor coactivator, promotes mitochondrial biogenesis, the fiber-type switch to oxidative fibers, and angiogenesis in skeletal muscle. Because exercise training induces these adaptations, together with increased PGC-1α, PGC-1α may contribute to the exercise-mediated change in phospholipid fatty acid composition. To determine the role of PGC-1α, we performed lipidomic analyses of skeletal muscle from genetically modified mice that overexpress PGC-1α in skeletal muscle or that carry KO alleles of PGC-1α. We found that PGC-1α affected lipid profiles in skeletal muscle and increased several phospholipid species in glycolytic muscle, namely phosphatidylcholine (PC) (18:0/22:6) and phosphatidylethanolamine (PE) (18:0/22:6). We also found that exercise training increased PC (18:0/22:6) and PE (18:0/22:6) in glycolytic muscle and that PGC-1α was required for these alterations. Because phospholipid fatty acid composition influences cell permeability and receptor stability at the cell membrane, these phospholipids may contribute to exercise training-mediated functional changes in the skeletal muscle.


Asunto(s)
Músculo Esquelético/metabolismo , Fosfolípidos/metabolismo , Condicionamiento Físico Animal/fisiología , Factores de Transcripción/metabolismo , Animales , Humanos , Masculino , Espectrometría de Masas , Ratones , Ratones Transgénicos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Factores de Transcripción/genética
6.
J Nutr Sci Vitaminol (Tokyo) ; 61(6): 441-8, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26875484

RESUMEN

Asparagine synthetase (ASNS), 3-phosphoglycerate dehydrogenase (PHGDH) and serine dehydratase (SDS) in rat liver are expressed in response to protein and amino acid intake. In the present study, we examined the expression of these enzymes in relation to amino acid imbalance caused by leucine. Rats were subjected to leucine administration in the diet or orally between meals. Consumption of more than 2% leucine in a 6% casein diet suppressed food intake and caused growth retardation in a dose-dependent manner, but this was not seen in a 12% or 40% casein diet. ASNS and PHGDH expression in the liver was significantly induced by the 6% casein diet and was suppressed by leucine in a dose-dependent manner, whereas the SDS expression was induced. These effects were leucine specific and not seen with ingestion of isoleucine or valine. However, leucine orally administered between meals did not change the food intake or growth of rats fed a 6% casein die, though it similarly affected the expression of ASNS, PHGDH and SDS in the liver. These results suggest that the growth retardation caused by leucine imbalance was mainly because of the suppression of food intake, and demonstrated that there are no causal relationships between ASNS, PHGDH and SDS expression and amino acid imbalance caused by leucine.


Asunto(s)
Aspartatoamoníaco Ligasa/metabolismo , Dieta , Ingestión de Alimentos/efectos de los fármacos , L-Serina Deshidratasa/metabolismo , Leucina/efectos adversos , Hígado/efectos de los fármacos , Fosfoglicerato-Deshidrogenasa/metabolismo , Aminoácidos/administración & dosificación , Aminoácidos/metabolismo , Animales , Peso Corporal , Caseínas/administración & dosificación , Regulación hacia Abajo , Ingestión de Energía/efectos de los fármacos , Crecimiento/efectos de los fármacos , Homeostasis/efectos de los fármacos , Isoleucina/farmacología , Leucina/administración & dosificación , Hígado/metabolismo , Masculino , Ratas Sprague-Dawley , Activación Transcripcional , Regulación hacia Arriba , Valina/farmacología
7.
Biosci Biotechnol Biochem ; 77(7): 1593-4, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23877616

RESUMEN

It is well known that large dose of leucine reduces the food intake and causes growth retardation in experimental animals when leucine is given with a low-protein diet. However, the mechanism for the anorectic effect of leucine has not yet been clarified. We demonstrate here that the anorectic effect of leucine was significantly reduced in a vagotomized rat.


Asunto(s)
Depresores del Apetito/farmacología , Dieta con Restricción de Proteínas/efectos adversos , Dieta , Leucina/farmacología , Vagotomía , Animales , Masculino , Ratas , Ratas Sprague-Dawley
8.
J Nutr Sci Vitaminol (Tokyo) ; 59(1): 45-55, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23535539

RESUMEN

The present study was conducted to identify reliable gene biomarkers for the adverse effects of excessive leucine (Leu) in Sprague-Dawley rats by DNA microarray. It has long been known that the adverse effects of excessive amino acid intake depend on dietary protein levels. Male rats were divided into 12 groups (n=6) and fed for 1 wk a diet containing low (6%), moderate (12%) or high (40%) protein. Different levels of Leu (0, 2, 4, and 8%) were added to the diets. Consumption of diets containing more than 4% Leu in 6% protein resulted in growth retardation and reduced liver weight, whereas the administration of the same dose of Leu with 12% or 40% protein did not affect them. By a process of systematic data extraction, 6 candidate gene markers were identified. The liver gene expression data obtained from another experiment with 0, 2, 3, 4, and 8% Leu in a low-protein diet was used to examine the validity of these biomarker candidates with receiver operating characteristic (ROC) curve analysis. All of AUC values of the biomarker candidates were more than 0.700, suggesting the effectiveness of the marker candidates as the indices of Leu excess. The cut-off value for the ROC curve of the gene-marker panel, which was obtained by multiple regression analysis of gene markers, indicated that Leu levels higher than 3% have adverse effects. In conclusion, the gene-marker panel suggested that for male rats dietary Leu supplementation of 2% is the NOAEL dose in low-protein (6%) diets.


Asunto(s)
Dieta con Restricción de Proteínas , Proteínas en la Dieta/administración & dosificación , Suplementos Dietéticos , Ingestión de Energía , Trastornos del Crecimiento/etiología , Leucina/efectos adversos , Hígado/efectos de los fármacos , Animales , Área Bajo la Curva , Biomarcadores/metabolismo , ADN/análisis , Dieta , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Marcadores Genéticos , Crecimiento/efectos de los fármacos , Crecimiento/genética , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/metabolismo , Leucina/administración & dosificación , Masculino , Análisis por Micromatrices , Tamaño de los Órganos , Curva ROC , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Análisis de Regresión , Transcriptoma
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