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mTOR AND Leucine

Yulong Tang, Bie Tan, Guangran Li, Jianjun Li, Peng Ji, Yulong Yin
Amino acid transporters play an important role in cell growth and metabolism. MeAIB, a transporter-selective substrate, often represses the adaptive regulation of sodium-coupled neutral amino acid transporter 2 (SNAT2), which may act as a receptor and regulate cellular amino acid contents, therefore modulating cellular downstream signaling. The aim of this study was to investigate the effects of MeAIB to SNAT2 on cell proliferation, protein turnover, and the mammalian target of rapamycin (mTOR) signaling pathway in porcine enterocytes...
March 2, 2018: International Journal of Molecular Sciences
Yan Wang, Caifu Luan, Guili Zhang, Chengming Sun
cMaf is a leucine-zipper transcription factor that is involved in cell differentiation, oncogenic transformation, and human diseases; however, the functions of cMaf in inflammatory responses in macrophages are still not fully understood. Western blot analysis showed that cMaf expression was induced by lipopolysaccharide (LPS) stimulation in mouse macrophages. An enzyme-linked immunosorbent assay was performed to detect the level of expression of inflammatory cytokines after knockdown of cMaf expression in macrophages using a small interfering RNA (siRNA)...
February 23, 2018: International Journal of Molecular Medicine
M L DeBoer, K M Martinson, M S Pampusch, A M Hansen, S M Wells, C Ward, M Hathaway
Leucine has been shown to stimulate the mammalian/mechanistic target of rapamycin (mTOR) signaling pathway which plays numerous key regulatory roles in cell growth, survival and metabolism including protein synthesis in a number of species. However, previous work with equine satellite cells has suggested distinct species differences in regards to physiological effects and the magnitude of responses to growth factors and regulators. Because there is limited research available regarding the role of leucine in regulating equine skeletal muscle protein synthesis, the objective of this study was to evaluate the effect of leucine on the mTOR signaling pathway in cultured equine satellite...
February 12, 2018: Journal of Animal Science
Yoriko Sato, Yusuke Sato, Reiko Suzuki, Kodwo Obeng, Fumiaki Yoshizawa
Mammalian target of rapamycin (mTOR) signaling controls skeletal muscle cell differentiation, growth, and metabolism by sensing the intracellular energy status and nutrients. Recently, leucyl-tRNA synthetase (Lars) was identified as an intracellular sensor of leucine involved in the activation of mTOR signaling. However, there is still no evidence for the activation of mTOR signaling by Lars and its physiological roles in skeletal muscle cells. In this study, we determined the potential roles of Lars for the activation of mTOR signaling, skeletal muscle cell differentiation, hypertrophy, and metabolism using small interfering (si)-RNA knockdown...
February 6, 2018: Experimental Cell Research
Bo Ruem Yoon, Yoon-Jeong Oh, Seong Wook Kang, Eun Bong Lee, Won-Woo Lee
Amino acids (AAs) are necessary nutrients which act not only as building blocks in protein synthesis but also in crucial anabolic cellular signaling pathways. It has been demonstrated that SLC7A5 is a critical transporter that mediates uptake of several essential amino acids in highly proliferative tumors and activated T cells. However, the dynamics and relevance of SLC7A5 activity in monocytes/macrophages is still poorly understood. We provide evidence that SLC7A5-mediated leucine influx contributes to pro-inflammatory cytokine production via mTOR complex 1 (mTORC1)-induced glycolytic reprograming in activated human monocytes/macrophages...
2018: Frontiers in Immunology
Laura Tedesco, Giovanni Corsetti, Chiara Ruocco, Maurizio Ragni, Fabio Rossi, Michele O Carruba, Alessandra Valerio, Enzo Nisoli
Chronic alcohol consumption promotes mitochondrial dysfunction, oxidative stress, defective protein metabolism, and fat accumulation in hepatocytes (liver steatosis). Inadequate amino-acid metabolism is worsened by protein malnutrition, frequently present in alcohol-consuming patients, with reduced circulating branched-chain amino acids (BCAAs). Here we asked whether dietary supplementation with a specific amino-acid mixture, enriched in BCAAs (BCAAem) and able to promote mitochondrial function in muscle of middle-aged rodents, would prevent mitochondrial dysfunction and liver steatosis in Wistar rats fed on a Lieber-DeCarli ethanol (EtOH)-containing liquid diet...
January 25, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
Nora López, Juana Sánchez, Andreu Palou, Francisca Serra
Early nutrition plays an important role in development and may constitute a relevant contributor to the onset of obesity in adulthood. The aim of this study was to evaluate the long-term impact of maternal leucine (Leu) supplementation during lactation on progeny in rats. A chow diet, supplemented with 2% Leu, was supplied during lactation (21 days) and, from weaning onwards, was replaced by a standard chow diet. Then, at adulthood (6 months of age), this was replaced with hypercaloric diets (either with high-fat (HF) or high-carbohydrate (HC) content), for two months, to induce obesity...
January 12, 2018: Nutrients
Yehui Duan, Fengna Li, Qiuping Guo, Wenlong Wang, Lingyu Zhang, Chaoyue Wen, Xiao'an Chen, Yulong Yin
Leucine (Leu) and its metabolites α-ketoisocaproate (KIC) and β-hydroxy-β-methyl butyrate (HMB) are potent regulators of protein turnover. The aim of this study was to compare the inhibitory effects of Leu, KIC, and HMB on protein degradation and to investigate the mechanisms involved. The results showed that the inhibitory effect of HMB (0.38 ± 0.04) was more potent than that of Leu (0.76 ± 0.04) and KIC (0.56 ± 0.04, P < 0.01), and was significantly abolished in the presence of LY294002 (1.48 ± 0...
January 10, 2018: Journal of Agricultural and Food Chemistry
Zhao Yu, Wang Lin, Zhang Rui, Pan Jihong
In rheumatoid arthritis (RA), activated synovial fibroblasts have the ability to invade joint cartilage, actively contributing to joint destruction in RA. The mechanisms underlying this cell migration and invasion remain unclear. Our previous results and data from the GEO profile indicate that the L-type amino acid transporter gene, LAT1, is overexpressed in the synovium of RA. To identify its potential role in RA, fibroblast-like synoviocytes (FLS) from patients with RA were used to determine the effects of suppressing the LAT1 genes using RNA interference and the LAT inhibitor, BCH...
February 2018: Amino Acids
Takumi Yamane, Yuka Morioka, Yasuyuki Kitaura, Ken Iwatsuki, Yoshiharu Shimomura, Yuichi Oishi
Branched-chain amino acids (BCAAs) exhibit many physiological functions. However, the potential link and mechanism between BCAA and skin function are unknown. We examined the effects of deletion of branched-chain α-keto acid dehydrogenase kinase (BDK), a key enzyme in BCAA catabolism, on type I and III tropocollagen syntheses in mice. Leucine and isoleucine levels were significantly lower in the skin of BDK-KO mice compared with wild-type mice. No changes in valine concentrations were observed. The levels of type I and III tropocollagen proteins and mRNAs (COL1A1 and COL3A1) were significantly lower in the skin of BDK-KO mice compared with wild-type mice...
December 1, 2017: Bioscience, Biotechnology, and Biochemistry
Alexander D Brown, Graeme L Close, Adam P Sharples, Claire E Stewart
Cell migration is central to skeletal muscle repair following damage. Leucine and β-Hydroxy β-methylbutyric acid (HMB) are supplements consumed for recovery from muscle damaging exercise in humans, however, their impact on muscle cell migration with age is not yet understood. We hypothesised that replicatively aged ("aged"; P46-P48) myoblasts would be less efficient at basal and supplemented repair versus parental controls ("control"; P12-P16). Aged and control myoblasts were scratch-damaged and migration velocity, directionality and distance assessed over 48 h in the absence and presence of leucine (10 mM) or HMB (10 mM) ± PI3K/Akt (LY294002 10 μM), ERK (PD98059 5 μM) or mTOR (rapamycin 0...
December 2017: Biogerontology
Z Xia, J M Cholewa, Y Zhao, Y Yang, H Shang, H Jiang, Q Su, N E Zanchi
Previous research has demonstrated the positive effects of concurrent/combined aerobic and resistance exercise or leucine supplementation on skeletal muscle protein synthesis (MPS) and hypertrophy in aging organisms. However, the effects of a multimodal intervention which combines both aerobic and resistance exercise and leucine supplementation has not been fully elucidated. Eighteen month old and 2 month old C57BL/6 mice were assigned to aging control (AC, n = 8), aging and multimodal intervention (AMI, n = 8) and young control (YC, n = 8)...
December 13, 2017: Food & Function
Sara Comesana, Cristina Velasco, Rosa M Ceinos, Marcos A Lopez-Patiño, Jesus M Miguez, Sofia Morais, Jose L Soengas
To assess the existence of central amino acid sensing systems in fish we carried out two experiments in rainbow trout. In the first one, we injected ICV two different branched-chain amino acids (BCAA), leucine and valine, and assessed food intake up to 48 h later. Leucine decreased and valine increased food intake. In a second experiment, 6h after similar ICV treatment we determined changes in parameters related to putative amino acid sensing systems. Amino acid sensing systems respond to leucine in hypothalamus and telencephalon, and to valine in telencephalon...
October 18, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Jong Hyun Kim, Chulho Lee, Minji Lee, Haipeng Wang, Kibum Kim, Seung Joon Park, Ina Yoon, Jayun Jang, Hanchao Zhao, Hoi Kyoung Kim, Nam Hoon Kwon, Seung Jae Jeong, Hee Chan Yoo, Jae Hyun Kim, Jee Sun Yang, Myeong Youl Lee, Chang Woo Lee, Jieun Yun, Soo Jin Oh, Jong Soon Kang, Susan A Martinis, Kwang Yeon Hwang, Min Guo, Gyoonhee Han, Jung Min Han, Sunghoon Kim
Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity...
September 29, 2017: Nature Communications
Kyosuke Nakayama, Atsushi Kanda, Ryoichi Tagawa, Chiaki Sanbongi, Shuji Ikegami, Hiroyuki Itoh
Bovine milk proteins have a low absorption rate due to gastric acid-induced coagulation. Acidified milk remains liquid under acidic conditions; therefore, the absorption rate of its protein may differ from that of untreated milk. To investigate how this would affect muscle protein synthesis (MPS), we compared MPS after ingestion of acidified versus skim milk in rats. Male Sprague-Dawley rats swam for 2 h and were immediately administered acidified or skim milk, then euthanized at 30, 60, 90, and 120 min afterwards...
September 27, 2017: Nutrients
Lu Li, Lijie Liu, Bo Qu, Xueying Li, Xuejun Gao, Minghui Zhang
Twinfilin1 (TWF1) is an actin monomer-binding protein, which biological function has not yet been fully uncovered. In our previous study, we found by mass spectrometry analysis that TWF1 might be one of the major proteins responsible for milk bio-synthesis and proliferation of bovine mammary epithelial cells (BMECs). The purpose of this study was to explore the possible mechanism by which TWF1 regulates signaling pathways that enhance milk bio-synthesis and proliferation of BMECs. We first explored the effects of TWF1 on milk bio-synthesis and cell proliferation, and analyzed the role of TWF1 on the protein levels of signaling molecules (mTOR, SREBP-1c and Cyclin D1) related to milk bio-synthesis and cell proliferation...
October 21, 2017: Biochemical and Biophysical Research Communications
Håkan Claes Rundqvist, Mona Esbjörnsson, Olav Rooyackers, Ted Osterlund, Marcus Moberg, William Apró, Eva Blomstrand, Eva Jansson
Nutrient ingestion is known to increase the exercise-induced stimulation of muscle protein synthesis following resistance exercise. Less is known about the effect of nutrients on muscle protein synthesis following sprint exercise. At two occasions separated by one month, twelve healthy subjects performed three 30-s sprints with 20-min rest between bouts. In randomized order, they consumed a drink with essential amino acids and maltodextrin (nutrient) or flavored water (placebo). Muscle biopsies were obtained 80 and 200 min after the last sprint and blood samples were taken repeatedly during the experiment...
August 31, 2017: Journal of Applied Physiology
Naoya Nakai, Fuminori Kawano, Taro Murakami, Ken Nakata, Kazuhiko Higashida
Branched-chain amino acid supplements consumed following exercise are widely used to increase muscle mass. Although both exercise (ie, mechanical stimulation) and branched-chain amino acid leucine supplementation have been reported to stimulate muscle protein synthesis by activating the mammalian target of rapamycin (mTOR) signaling pathway independently, the mechanisms underlying their synergistic effects are largely unknown. Utilizing cultured differentiated C2C12 myotubes, we established a combination treatment model in which the cells were subjected to cyclic uniaxial mechanical stretching (4 h, 15%, 1 Hz) followed by stimulation with 2 mM leucine for 45 min...
August 30, 2017: Journal of Cellular Biochemistry
Zhen Zhen, Minghui Zhang, Xiaohan Yuan, Bo Qu, Yanbo Yu, Xuejun Gao, Youwen Qiu
Milk synthesis of bovine mammary gland is a complex biological process that is regulated by hormones and nutrients, but the mechanism of these regulations still needs further research. DEAD-box helicase 6 (DDX6) is an important member of the RNA helicase family, involved in the regulation of mRNA storage and translation in different systems, but its physiological role and mechanism are largely unclear. In this study, we describe DDX6 as a potentially novel negative regulator for milk synthesis and proliferation of bovine mammary epithelial cells (BMECs)...
August 25, 2017: In Vitro Cellular & Developmental Biology. Animal
Dong-Dong Cheng, Shi-Jie Li, Bin Zhu, Ting Yuan, Qing-Cheng Yang, Cun-Yi Fan
Osteosarcoma is the most common malignant bone tumor in adolescents. The function of basic leucine zipper and W2 domains 2 (BZW2) in tumor progression has been reported. However, the role and mechanisms of BZW2 in osteosarcoma remain to be determined. The aim of the present study was to reveal the expression and biological functions of BZW2 in osteosarcoma and to elucidate the proximal mechanisms underlying these functions. The expression of BZW2 in osteosarcoma tissues and cell lines was assessed by qRT-PCR, western blotting and immunohistochemistry...
October 2017: Oncology Reports
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