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Linda H Bergersen - One of the best experts on this subject based on the ideXlab platform.
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upregulation of the lactate Transporter Monocarboxylate Transporter 1 at the blood brain barrier in a rat model of attention deficit hyperactivity disorder suggests hyperactivity could be a form of self treatment
Behavioural Brain Research, 2019Co-Authors: Tirill Medin, Linda H Bergersen, Hege Medin, Marita Brandsar Hefte, Jon StormmathisenAbstract:Abstract The energy deficit hypothesis of attention-deficit/hyperactivity disorder (ADHD) suggests that low lactate production by brain astrocytes causes the symptoms of the disorder. Astrocytes are the main producers of lactate in the brain; however, skeletal muscles can produce the most lactate in the body. The lactate production by skeletal muscles increases with physical activity, as does the expression of the lactate Transporter Monocarboxylate Transporter 1 (MCT1) at the blood-brain barrier (BBB). We hypothesise that children with ADHD, by being hyperactive, increase lactate production by skeletal muscles and transport it into the brain to compensate for low supply by astrocytes. The aim of this study was to explore whether the level of MCT1 is altered in the brain in an animal model of ADHD. The MCT1 expression was quantified on hippocampal brain sections from the best available rat model of ADHD, i.e., the spontaneously hypertensive rat (SHR) (n = 12), and the relevant control, the Wistar Kyoto rat (WKY) (n = 12), by the use of quantitative immunofluorescence laser scanning microscopy and postembedding immunogold electron microscopy. The results revealed significantly higher levels of hippocampal MCT1 immunoreactivity in SHR compared to WKY, particularly at the BBB. These results indicate that lactate flux through MCT1 between the body and the brain could be upregulated in children with ADHD. This study adds to previous research suggesting hyperactivity may be beneficial in ADHD; Children with ADHD possibly display a hyperactive behaviour in order to raise skeletal muscle lactate production, MCT1 expression and flux over the BBB to supply the brain with lactate.
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Upregulation of the lactate Transporter Monocarboxylate Transporter 1 at the blood-brain barrier in a rat model of attention-deficit/hyperactivity disorder suggests hyperactivity could be a form of self-treatment.
Behavioural Brain Research, 2018Co-Authors: Tirill Medin, Hege Medin, Marita Brandsar Hefte, Jon Storm-mathisen, Linda H BergersenAbstract:Abstract The energy deficit hypothesis of attention-deficit/hyperactivity disorder (ADHD) suggests that low lactate production by brain astrocytes causes the symptoms of the disorder. Astrocytes are the main producers of lactate in the brain; however, skeletal muscles can produce the most lactate in the body. The lactate production by skeletal muscles increases with physical activity, as does the expression of the lactate Transporter Monocarboxylate Transporter 1 (MCT1) at the blood-brain barrier (BBB). We hypothesise that children with ADHD, by being hyperactive, increase lactate production by skeletal muscles and transport it into the brain to compensate for low supply by astrocytes. The aim of this study was to explore whether the level of MCT1 is altered in the brain in an animal model of ADHD. The MCT1 expression was quantified on hippocampal brain sections from the best available rat model of ADHD, i.e., the spontaneously hypertensive rat (SHR) (n = 12), and the relevant control, the Wistar Kyoto rat (WKY) (n = 12), by the use of quantitative immunofluorescence laser scanning microscopy and postembedding immunogold electron microscopy. The results revealed significantly higher levels of hippocampal MCT1 immunoreactivity in SHR compared to WKY, particularly at the BBB. These results indicate that lactate flux through MCT1 between the body and the brain could be upregulated in children with ADHD. This study adds to previous research suggesting hyperactivity may be beneficial in ADHD; Children with ADHD possibly display a hyperactive behaviour in order to raise skeletal muscle lactate production, MCT1 expression and flux over the BBB to supply the brain with lactate.
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altered expression of brain Monocarboxylate Transporter 1 in models of temporal lobe epilepsy
Neurobiology of Disease, 2012Co-Authors: Fredrik Lauritzen, Edgar Perez, Eric R Melillo, Hitten P Zaveri, Yue Wang, Linda H BergersenAbstract:Monocarboxylate Transporter 1 (MCT1) facilitates the transport of Monocarboxylate fuels (lactate, pyruvate and ketone bodies) and acidic drugs, such as valproic acid, across cell membranes. We recently reported that MCT1 is deficient on microvessels in the epileptogenic hippocampal formation in patients with medication-refractory temporal lobe epilepsy (TLE). To further define the role of MCT1 in the pathophysiology of TLE, we used immunohistochemistry and stereological analysis to localize and quantify the Transporter in the hippocampal formation in three novel and highly relevant rat models of TLE and in nonepileptic control animals. One model utilizes methionine sulfoximine to induce brain glutamine synthetase deficiency and recurrent limbic seizures, while two models employ an episode of perforant pathway stimulation to cause epilepsy. MCT1 was lost on microvessels and upregulated on astrocytes in the hippocampal formation in all models of TLE. Notably, the loss of MCT1 on microvessels was not due to a reduction in microvessel density. The similarities in MCT1 expression among human subjects with TLE and several animal models of the disease strongly suggest a critical role of this molecule in the pathogenesis of TLE. We hypothesize that the downregulation of MCT1 may promote seizures via impaired uptake of ketone bodies and antiepileptic drugs by the epileptogenic brain. We also propose that the overexpression of MCT1 on astrocytes may lead to increased uptake or release of Monocarboxylates by these cells, with important implications for brain metabolism and excitability. These hypotheses can now be rigorously tested in several animal models that replicate key features of human TLE.
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Monocarboxylate Transporter 1 is deficient on microvessels in the human epileptogenic hippocampus
Neurobiology of Disease, 2011Co-Authors: Fredrik Lauritzen, Nihal C De Lanerolle, Dennis D Spencer, Linda H BergersenAbstract:Abstract Monocarboxylate Transporter 1 (MCT1) facilitates the transport of important metabolic fuels (lactate, pyruvate and ketone bodies) and possibly also acidic drugs such as valproic acid across the blood–brain barrier. Because an impaired brain energy metabolism and resistance to antiepileptic drugs are common features of temporal lobe epilepsy (TLE), we sought to study the expression of MCT1 in the brain of patients with this disease. Immunohistochemistry and immunogold electron microscopy were used to assess the distribution of MCT1 in brain specimens from patients with TLE and concomitant hippocampal sclerosis (referred to as mesial TLE or MTLE (n = 15)), patients with TLE and no hippocampal sclerosis (non-MTLE, n = 13) and neurologically normal autopsy subjects (n = 8). MCT1 was present on an extensive network of microvessels throughout the hippocampal formation in autopsy controls and to a lesser degree in non-MTLE. Patients with MTLE were markedly deficient in MCT1 on microvessels in several areas of the hippocampal formation, especially CA1, which exhibited a 37% to 48% loss of MCT1 on the plasma membrane of endothelial cells when compared with non-MTLE. These findings suggest that the uptake of blood-derived Monocarboxylate fuels and possibly also acidic drugs, such as valproic acid, is perturbed in the epileptogenic hippocampus, particularly in MTLE. We hypothesize that the loss of MCT1 on brain microvessels is mechanistically involved in the pathophysiology of drug-resistant TLE, and propose that re-expression of MCT1 may represent a novel therapeutic approach for this disease.
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Cross-reinnervation changes the expression patterns of the Monocarboxylate Transporters 1 and 4: An experimental study in slow and fast rat skeletal muscle.
Neuroscience, 2006Co-Authors: Linda H Bergersen, Andrew P. Halestrap, Marion J. Thomas, E. Jóhannsson, O. Wærhaug, K. Andersen, Ole M. Sejersted, O.p. OttersenAbstract:The Monocarboxylate Transporters 1 and 4 are expressed in brain as well as in skeletal muscle and play important roles in the energy metabolism of both tissues. In brain, Monocarboxylate Transporter 1 occurs in astrocytes, ependymocytes, and endothelial cells while Monocarboxylate Transporter 4 appears to be restricted to astrocytes. In muscle, Monocarboxylate Transporter 1 is enriched in oxidative muscle fibers whereas Monocarboxylate Transporter 4 is expressed in all fibers, with the lowest levels in oxidative fiber types. The mechanisms regulating Monocarboxylate Transporter 1 and Monocarboxylate Transporter 4 expression are not known. We hypothesized that the expression of these Transporters would be sensitive to long term changes in metabolic activity level. This hypothesis can be tested in rat skeletal muscle, where permanent changes in activity level can be induced by cross-reinnervation. We transplanted motor axons originally innervating the fast-twitch extensor digitorum longus muscle to the slow-twitch soleus muscle and vice versa. Four months later, microscopic analysis revealed transformation of muscle fiber types in the cross-reinnervated muscles. Western blot analysis showed that Monocarboxylate Transporter 1 was increased by 140% in extensor digitorum longus muscle and decreased by 30% in soleus muscle after cross-reinnervation. In contrast, cross-reinnervation induced a 62% decrease of Monocarboxylate Transporter 4 in extensor digitorum longus muscle and a 1300% increase in soleus muscle. Our findings show that cross-reinnervation causes pronounced changes in the expression levels of Monocarboxylate Transporter 1 and Monocarboxylate Transporter 4, probably as a direct consequence of the new pattern of nerve impulses. The data indicate that the mode of innervation dictates the expression of Monocarboxylate Transporter proteins in the target cells and that the change in Monocarboxylate Transporter isoform profile is an integral part of the muscle fiber transformation that occurs after cross-reinnervation. Our findings support the hypothesis that the expression of Monocarboxylate Transporter 1 and Monocarboxylate Transporter 4 in excitable tissues is regulated by activity.
Hideo Hatta - One of the best experts on this subject based on the ideXlab platform.
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Chronic post-exercise lactate administration with endurance training increases glycogen concentration and Monocarboxylate Transporter 1 protein in mouse white muscle.
Journal of Nutritional Science and Vitaminology, 2015Co-Authors: Daisuke Hoshino, Tatsuya Hanawa, Yumiko Takahashi, Hiroyuki Masuda, Mai Kato, Hideo HattaAbstract:: Lactate is oxidized as an energy fuel during exercise, and it also plays a key role in the regulation of glycogen synthesis in the muscles and liver after exercise. Previous studies have suggested that lactate is converted to glycogen and stimulates glycogen synthesis. However, it remains unclear whether chronic post-exercise lactate administration can increase glycogen storage in skeletal muscle. We examined whether 3 wk of chronic post-exercise lactate administration with training can increase muscle glycogen storage and whether such changes are associated with Monocarboxylate Transporter 1 (MCT1) protein expression in mice. Mice were assigned to receive saline with training (SA+T group; n=6) or lactate with training (LA+T group; n=6). All mice performed 40 min of treadmill running at 25 m/min, following which they received saline or lactate (2.5 mg/g body weight), 6 d/wk for 3 wk. After 3 wk, glycogen concentration at rest was higher in the white tibialis anterior (TA; p
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chronic post exercise lactate administration with endurance training increases glycogen concentration and Monocarboxylate Transporter 1 protein in mouse white muscle
Journal of Nutritional Science and Vitaminology, 2014Co-Authors: Daisuke Hoshino, Tatsuya Hanawa, Yumiko Takahashi, Hiroyuki Masuda, Mai Kato, Hideo HattaAbstract:: Lactate is oxidized as an energy fuel during exercise, and it also plays a key role in the regulation of glycogen synthesis in the muscles and liver after exercise. Previous studies have suggested that lactate is converted to glycogen and stimulates glycogen synthesis. However, it remains unclear whether chronic post-exercise lactate administration can increase glycogen storage in skeletal muscle. We examined whether 3 wk of chronic post-exercise lactate administration with training can increase muscle glycogen storage and whether such changes are associated with Monocarboxylate Transporter 1 (MCT1) protein expression in mice. Mice were assigned to receive saline with training (SA+T group; n=6) or lactate with training (LA+T group; n=6). All mice performed 40 min of treadmill running at 25 m/min, following which they received saline or lactate (2.5 mg/g body weight), 6 d/wk for 3 wk. After 3 wk, glycogen concentration at rest was higher in the white tibialis anterior (TA; p<0.05, +34%), but not in the red TA, in the LA+T group. Protein expression of MCT1, the primary lactate Transporter, was increased with chronic post-exercise lactate administration in the white TA (p<0.05, +32%), but not in the red TA. MCT1 protein expression was significantly correlated with muscle glycogen concentration in the red and white TA in both groups (p<0.05, r=0.969). These results suggest that chronic lactate administration after exercise increases MCT1 protein expression, which can be involved in the regulation of the observed increase in muscle glycogen storage after exercise training.
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Exercise training alleviates MCT1 and MCT4 reductions in heart and skeletal muscles of STZ-induced diabetic rats.
Journal of Applied Physiology, 2003Co-Authors: Taisuke Enoki, Hideo Hatta, Yuko Yoshida, Arend BonenAbstract:We compared the changes in Monocarboxylate Transporter 1 (MCT1) and 4 (MCT4) proteins in heart and skeletal muscles in sedentary control and streptozotocin (STZ)-induced diabetic rats (3 wk) and in...
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Exercise training alleviates MCT1 and MCT4 reductions in heart and skeletal muscles of STZ-induced diabetic rats.
Journal of Applied Physiology, 2003Co-Authors: Taisuke Enoki, Hideo Hatta, Yuko Yoshida, Arend BonenAbstract:We compared the changes in Monocarboxylate Transporter 1 (MCT1) and 4 (MCT4) proteins in heart and skeletal muscles in sedentary control and streptozotocin (STZ)-induced diabetic rats (3 wk) and in trained (3 wk) control and STZ-induced diabetic animals. In nondiabetic animals, training increased MCT1 in the plantaris (+51%; P 0.05) but were markedly greater than in the sedentary diabetic animals [MCT1: plantaris +63%, soleus +51%, heart +51% (P > 0....
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decreased Monocarboxylate Transporter 1 in rat soleus and edl muscles exposed to clenbuterol
Journal of Applied Physiology, 2001Co-Authors: Takashi Kitaura, Naoko Tsunekawa, Hideo HattaAbstract:We hypothesized that a shift in muscle fiber type induced by clenbuterol would change Monocarboxylate Transporter 1 (MCT1) content and activity of lactate dehydrogenase (LDH) and isoform pattern an...
Marilyn E Morris - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of the Monocarboxylate Transporter 1 inhibitor azd3965 in mice potential enterohepatic circulation and target mediated disposition
Pharmaceutical Research, 2020Co-Authors: Xiaowen Guan, Marilyn E MorrisAbstract:To evaluate the pharmacokinetics (PK) of the Monocarboxylate Transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drug disposition (TMDD) of AZD3965. Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100 mg/kg) or oral gavage (100 mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses. AZD3965 exhibited a large volume of distribution and rapid oral absorption, with a high oral bioavailability. Prominent reentry peaks were observed after both oral and IV administration, suggesting potential EHC of AZD3965 or of a potential glucuronide conjugate. The dose-dependent studies indicated greater than proportional increases in exposure, an increase in the terminal half-life, and decrease in clearance and volume of distribution with increasing IV doses, indicating nonlinear pharmacokinetics and potential TMDD of AZD3965. Mechanistic compartmental models were developed to characterize the complex pharmacokinetics of AZD3965. The current study represents the first comprehensive report of the pharmacokinetics of AZD3965 in mice, indicating the potential contribution of EHC and TMDD in the disposition of AZD3965.
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treatment of γ hydroxybutyric acid and γ butyrolactone overdose with two potent Monocarboxylate Transporter 1 inhibitors azd3965 and ar c155858
Journal of Pharmacology and Experimental Therapeutics, 2019Co-Authors: Kristin E Follman, Marilyn E MorrisAbstract:The illicit use of γ-hydroxybutyric acid (GHB), and its prodrug, γ-butyrolactone (GBL), results in severe adverse effects including sedation, coma, respiratory depression, and death. Current treatment of GHB/GBL overdose is limited to supportive care. Recent reports indicate that GHB-related deaths are on the rise; a specific treatment may reduce lethality associated with GHB/GBL. Pretreatment with inhibitors of Monocarboxylate Transporter 1 (MCT1), a Transporter that mediates many of the processes involved in the absorption, distribution (including brain uptake), and elimination of GHB/GBL, has been shown to prevent GHB-induced respiratory depression by increasing the renal clearance of GHB. To identify whether MCT1 inhibition is an effective treatment of GHB overdose, the impact of two MCT1 inhibitors, (S)-5-(4-hydroxy-4-methylisoxazolidine-2-carbonyl)-1-isopropyl-3-methyl-6-((3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)thieno[2,3-day]pyrimidine-2,4(1H,3H)-dione (AZD3965) and 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[[(4S)-4-hydroxy-2-isoxazolidinyl]carbonyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-day]pyrimidine2,4(1H,3H)-dione (AR-C155858), on the toxicokinetics and toxicodynamics of GHB/GBL was assessed when the administration of the inhibitor was delayed 60 and 120 minutes (post-treatment) after administration of GHB/GBL. AR-C155858 and AZD3965 reduced the toxicodynamic effects of GHB when GHB was administered intravenously, orally, or orally as the prodrug GBL. The impact of these inhibitors on GHB toxicokinetics was dependent on the route of GHB administration and the delay between GHB/GBL administration and administration of the MCT1 inhibitor. The reduction in GHB plasma exposure did not explain the observed effect of MCT1 inhibition on GHB-induced respiratory depression. The efficacy of MCT1 inhibition on GHB toxicodynamics is likely driven by the pronounced reduction in GHB brain concentrations. Overall, this study indicates that inhibition of MCT1 is an effective treatment of GHB/GBL overdose.
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In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model
The AAPS Journal, 2018Co-Authors: Xiaowen Guan, Mark A. Bryniarski, Marilyn E MorrisAbstract:Monocarboxylate Transporter 1 (MCT1), also known as a l -lactate Transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression. AR-C155858 inhibited the cellular l -lactate uptake and cellular proliferation at low nanomolar potencies (IC_50 values of 25.0 ± 4.2 and 20.2 ± 0.2 nM, respectively). In the xenograft 4T1 mouse model of immunocompetent animals, AR-C155858 (10 mg/kg i.p. once daily) had no effect on tumor volume and weight. Treatment with AR-C155858 resulted in slightly increased tumor lactate concentrations; however, the changes were not statistically significant. AR-C155858 was well tolerated, as demonstrated by the unchanged body weight and blood lactate concentrations. Average blood and tumor AR-C155858 concentrations (110 ± 22 and 574 ± 245 nM, respectively), 24 h after the last dose, were well above the IC_50 values. These data indicate that AR-C155858 penetrated 4T1 xenograft tumors and was present at high concentrations but was ineffective in decreasing tumor growth. Evaluations of AR-C155858 in other preclinical models of breast cancer are needed to further assess its efficacy.
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flavonoids modulate Monocarboxylate Transporter 1 mediated transport of γ hydroxybutyrate in vitro and in vivo
Drug Metabolism and Disposition, 2007Co-Authors: Qi Wang, Marilyn E MorrisAbstract:The objective of this study was to determine the effects of flavonoids on the in vitro Monocarboxylate Transporter 1 (MCT1)-mediated transport and in vivo disposition of the drug of abuse, γ-hydroxybutyrate (GHB). The uptake of GHB in rat MCT1 gene-transfected MDA-MB231 cells was significantly decreased in the presence of the flavonoids apigenin, biochanin A, chrysin, diosemin, fisetin, genistein, hesperitin, kaempferol, luteolin, morin, narigenin, phloretin, and quercetin, but was not affected by the flavonoid glycosides phloridzin and rutin. The IC50 values for luteolin, morin, and phloretin were 0.41 ± 0.14, 6.41 ± 2.01, and 2.57 ± 0.48 μM, with the inhibition mechanism for luteolin being competitive. [3H]Kaempferol and [3H]biochanin A did not exhibit MCT1-mediated uptake, suggesting that these flavonoids are not substrates for MCT1. The combination of luteolin and phloretin inhibited the uptake of GHB in a synergistic manner; however, the combination of luteolin and morin was antagonistic. GHB 1000 mg/kg was administered to rats by i.v. bolus, with or without the concomitant administration of luteolin 10 mg/kg i.v. After luteolin treatment, the renal and total clearances of GHB were significantly increased, probably because of inhibition of the MCT1-mediated renal reabsorption of GHB, and the sleep time significantly decreased (121 ± 5 min versus 165 ± 10 min) compared with control rats. Overall, the results of this study indicate that flavonoids from food or herbal products may significantly alter the pharmacokinetics and pharmacodynamics of MCT substrates.
Pierre J Magistretti - One of the best experts on this subject based on the ideXlab platform.
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Impact of MCT1 Haploinsufficiency on the Mouse Retina.
Advances in Experimental Medicine and Biology, 2018Co-Authors: Neal S. Peachey, Sylvain Lengacher, Pierre J Magistretti, Luc Pellerin, Minzhong Yu, Nancy J. PhilpAbstract:The Monocarboxylate Transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1 +/− heterozygotes, which express half of the normal complement of MCT1. The MCT1 +/− retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism.
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deficiency in Monocarboxylate Transporter 1 mct1 in mice delays regeneration of peripheral nerves following sciatic nerve crush
Experimental Neurology, 2015Co-Authors: Brett M Morrison, Sylvain Lengacher, Pierre J Magistretti, Akivaga Tsingalia, Luc Pellerin, Svetlana Vidensky, Mohamed H Farah, Jeffrey D RothsteinAbstract:Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, Monocarboxylate Transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. (C) 2014 Elsevier Inc. All rights reserved.
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Monocarboxylate Transporter 1 mct1 is critical for regeneration in peripheral nerves i6 1 001
Neurology, 2014Co-Authors: Brett M Morrison, Sylvain Lengacher, Pierre J Magistretti, Akivaga Tsingalia, Luc Pellerin, Jeffrey D RothsteinAbstract:OBJECTIVE: Investigate whether lactate Transporters, specifically Monocarboxylate Transporter 1 (MCT1), are necessary for peripheral nerve regeneration. BACKGROUND: Axons, particularly regenerating axons, have high metabolic demands in order to maintain critical functions such as axon transport and membrane depolarization. Though some of the required energy likely comes from extracellular glucose, we hypothesize that metabolic energy is also supplied locally by lactate, as has recently been recently shown in the CNS. In order to be transported across membranes, lactate requires specific MCTs, the most abundant of which in the nervous system is MCT1. DESIGN/METHODS: In the current study, we investigate the localization of MCT1 in the peripheral nerve and the capacity for nerve regeneration following sciatic nerve crush in MCT1 heterozygote null mice. RESULTS: We find that MCT1 is primarily expressed by perineurial cells in the peripheral nerve and is not upregulated following crush in Schwann cells, macrophages, or neurons. MCT1 heterozygote null mice, which have reduced MCT1 expression and capacity to upregulate MCT1 following injury, have a dramatic delay in regeneration of nerve fibers following sciatic crush injury. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In addition, muscle fibers remain 40% more atrophic at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. Finally, the number of regenerated axons in the sural nerve of MCT1 heterozygote null mice is significantly reduced compared to wild-type mice. CONCLUSIONS: These experiments demonstrate, for the first time, that MCT1 in perineurial cells is critical for peripheral nerve regeneration. We expect these experiments to lead not only to a greater understanding of nerve regeneration, but also to the development of novel agents to accelerate nerve regrowth in axonal neuropathies or following nerve trauma. Disclosure: Dr. Morrison has nothing to disclose. Dr. Tsingalia has nothing to disclose. Dr. Lengacher has nothing to disclose. Dr. Pellerin has nothing to disclose. Dr. Magistretti has nothing to disclose. Dr. Rothstein has received personal compensation for activities with Psyadon Pharmaceuticals, Cytokinetics, and Vertex.
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resistance to diet induced obesity and associated metabolic perturbations in haploinsufficient Monocarboxylate Transporter 1 mice
PLOS ONE, 2013Co-Authors: Sylvain Lengacher, Touria Nehirisitayeb, Nadia Steiner, Lionel Carneiro, Celine Favrod, Frederic Preitner, Bernard Thorens, Jean Christophe Stehle, Francois P Pralong, Pierre J MagistrettiAbstract:The Monocarboxylate Transporter 1 (MCT1 or SLC16A1) is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues. Genetically modified C57BL/6J mice were produced by targeted disruption of the mct1 gene in order to understand the role of this Transporter in energy homeostasis. Null mutation was embryonically lethal, but MCT1+/− mice developed normally. However, when fed high fat diet (HFD), MCT1+/− mice displayed resistance to development of diet-induced obesity (24.8% lower body weight after 16 weeks of HFD), as well as less insulin resistance and no hepatic steatosis as compared to littermate MCT1+/+ mice used as controls. Body composition analysis revealed that reduced weight gain in MCT1+/− mice was due to decreased fat accumulation (50.0% less after 9 months of HFD) notably in liver and white adipose tissue. This phenotype was associated with reduced food intake under HFD (12.3% less over 10 weeks) and decreased intestinal energy absorption (9.6% higher stool energy content). Indirect calorimetry measurements showed ∼ 15% increase in O2 consumption and CO2 production during the resting phase, without any changes in physical activity. Determination of plasma concentrations for various metabolites and hormones did not reveal significant changes in lactate and ketone bodies levels between the two genotypes, but both insulin and leptin levels, which were elevated in MCT1+/+ mice when fed HFD, were reduced in MCT1+/− mice under HFD. Interestingly, the enhancement in expression of several genes involved in lipid metabolism in the liver of MCT1+/+ mice under high fat diet was prevented in the liver of MCT1+/− mice under the same diet, thus likely contributing to the observed phenotype. These findings uncover the critical role of MCT1 in the regulation of energy balance when animals are exposed to an obesogenic diet.
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comparison of lactate transport in astroglial cells and Monocarboxylate Transporter 1 mct 1 expressing xenopus laevis oocytes expression of two different Monocarboxylate Transporters in astroglial cells and neurons
Journal of Biological Chemistry, 1997Co-Authors: Stefan Broer, Basim Rahman, Bernd Hamprecht, Luc Pellerin, Gioranni Pellegri, Jeanluc Martin, Stephan Verleysdonk, Pierre J MagistrettiAbstract:Abstract The transport of lactate is an essential part of the concept of metabolic coupling between neurons and glia. Lactate transport in primary cultures of astroglial cells was shown to be mediated by a single saturable transport system with aK m value for lactate of 7.7 mm and aV max value of 250 nmol/(min × mg of protein). Transport was inhibited by a variety of Monocarboxylates and by compounds known to inhibit Monocarboxylate transport in other cell types, such as α-cyano-4-hydroxycinnamate andp-chloromercurbenzenesulfonate. Using reverse transcriptase-polymerase chain reaction and Northern blotting, the presence of mRNA coding for the Monocarboxylate Transporter 1 (MCT1) was demonstrated in primary cultures of astroglial cells. In contrast, neuron-rich primary cultures were found to contain the mRNA coding for the Monocarboxylate Transporter 2 (MCT2). MCT1 was cloned and expressed in Xenopus laevis oocytes. Comparison of lactate transport in MCT1 expressing oocytes with lactate transport in glial cells revealed that MCT1 can account for all characteristics of lactate transport in glial cells. These data provide further molecular support for the existence of a lactate shuttle between astrocytes and neurons.
Martin O Leach - One of the best experts on this subject based on the ideXlab platform.
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Monocarboxylate Transporter 1 blockade with azd3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration
British Journal of Cancer, 2020Co-Authors: Mounia Belouechebabari, Teresa Casals Galobart, Teresa Delgadogoni, Slawomir Wantuch, Harold G Parkes, Debbie Tandy, James A Harker, Martin O LeachAbstract:BACKGROUND: Monocarboxylate Transporter 1 (MCT1) is a regulator of cell metabolism and a therapeutic target for cancer treatment. Understanding the changes in tumour function accompanying MCT1 inhibition will better characterise the anti-tumour effects of MCT1 inhibitors, potentially enabling the identification of pharmacodynamic biomarkers for the clinical development of these agents. METHODS: We assessed the impact of the MCT1 inhibitor AZD3965 on tumour metabolism and immune cell infiltration as key determinants of tumour biological function in the MCT1-dependent Raji B cell lymphoma model. RESULTS: Treatment of Raji xenograft-bearing severe combined immunodeficiency mice with AZD3965 led to inhibition of tumour growth paralleled with a decrease in tumour choline, as detected by non-invasive in vivo proton nuclear magnetic resonance spectroscopy. This effect was attributed to inhibition of phosphocholine de novo synthesis following decreased choline kinase α protein and messenger RNA expression that correlated with the AZD3965-induced build-up in intracellular lactate. These changes were concomitant with increased tumour immune cell infiltration involving dendritic and natural killer cells. CONCLUSIONS: Our data provide new insights into the metabolic and cellular changes that occur in the tumour microenvironment following MCT1 blockade, which may contribute to the anti-tumour activity of AZD3965 and could have potential as pharmacodynamic biomarkers of MCT1 inhibition.
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abstract 444 Monocarboxylate Transporter 1 inhibition with azd3965 increases cancer cell dependence on bioenergetic metabolism predicating combination therapy with mitochondrial inhibitors
Cancer Research, 2017Co-Authors: Mounia Belouechebabari, Teresa Casals Galobart, Slawomir Wantuch, Paul D Smith, Martin O LeachAbstract:Monocarboxylate Transporters (MCTs) are key mediators of lactate transport that have emerged as promising targets for anti-cancer therapy. The MCT1 inhibitor AZD3965 (AstraZeneca) has shown promising activity in various pre-clinical models and is currently in phase I/II clinical testing. Understanding the impact of this drug on tumour cell metabolism may unravel dependencies that could be exploited for combination therapy. Here we investigate changes in glucose metabolism induced by AZD3965 treatment using 13C NMR isotopomer analysis, and examine their significance for cell survival using mitochondrial metabolism inhibitors. Exposure of Raji human lymphoma cells to AZD3965 in media supplemented with [1-13C]glucose led to a marked reduction in glucose uptake and lactate production in the cellular growth media alongside a build-up in intracellular [3- 13C]lactate and [1-13C]glucose levels, indicative of blockade of lactate excretion and inhibition of overall glycolytic activity. These effects were concomitant with increased [4-13C]glutamate levels, consistent with re-routing of pyruvate towards mitochondrial metabolism and enhanced flux through oxidative pyruvate dehydrogenase. Further, AZD3965 treatment was paralleled with a significant increase in levels of steady state Krebs cycle-related metabolites (including succinate, fumarate, acetate and NAD+/NADH) and cellular ATP, as revealed by bioluminescent and 1H NMR analyses, indicating improved mitochondrial metabolism and cellular re-energization. Co-administration of the mitochondrial complex I inhibitor metformin or the mitochondrial pyruvate carrier inhibitor UK5099 markedly potentiated the anti-proliferative effects of AZD3965 and led to significantly increased cell death, indicating that the observed upregulation in mitochondrial metabolism was necessary to maintain cell survival under MCT1 inhibitor-induced metabolic stress. Similar effects were observed with a second human lymphoma cell line, Hut78. Our findings show that MCT1 inhibition leads to a shift in cellular metabolism towards mitochondrial bioenergetic metabolism, creating a metabolic vulnerability that could be exploited for combinatorial therapy to increase the efficacy of AZD3965. Citation Format: Mounia Beloueche-Babari, Teresa Casals Galobart, Slawomir Wantuch, Paul D. Smith, Martin O. Leach. Monocarboxylate Transporter 1 inhibition with AZD3965 increases cancer cell dependence on bioenergetic metabolism predicating combination therapy with mitochondrial inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 444. doi:10.1158/1538-7445.AM2017-444
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abstract c113 the Monocarboxylate Transporter 1 mct1 inhibitor azd3965 triggers mct4 dependent lactate accumulation and blocks pyruvate lactate exchange in human cancer cells
Molecular Cancer Therapeutics, 2015Co-Authors: Mounia Belouechebabari, Slawomir Wantuch, Paul D Smith, Markella Koniordou, Harry G Parkes, Vaitha Arunan, Thomas R Eykyn, Martin O LeachAbstract:Background: Monocarboxylate Transporters (MCTs) are key modulators of lactate homeostasis and represent promising metabolic targets for molecular cancer therapeutics. The MCT1 inhibitor AZD3965 is now in clinical trial and understanding the impact of this drug on tumour cell metabolism may enable the discovery of pharmacodynamic (PD) biomarkers of target inhibition that will support the clinical development of such agents. Since MCT1 mediates the bidirectional transport of lactate and other Monocarboxylates including pyruvate, here we use NMR spectroscopy to investigate the effect of AZD3965 on a) intracellular lactate levels and b) hyperpolarized 13 C-pyruvate-lactate exchange, as biomarkers for MCT1 inhibition in human cancer cells with varying MCT4 expression (predictive of resistance to AZD3965). Materials and Methods: Human Raji (MCT4-) and Hut78 (MCT4 low (+)) lymphoma as well as HT29 (MCT4 high (+++)) colon carcinoma cells were treated with either 5nM or 500nM AZD3965 for 24h and levels of intracellular lactate determined by 1 H NMR of cell extracts. Raji cells were also exposed to additional AZD3965 concentrations spanning 1nM-500nM. For 13 C-pyruvate-lactate exchange studies, Raji cells were treated with either 5nM or 25nM AZD3965 for 24h. Cells were then incubated at 37°C in FBS-free medium and dynamic 13 C NMR spectra acquired for 4 minutes with 2s intervals immediately after the addition of 10mM hyperpolarised [1- 13 C]pyruvic acid and 10mM unlabelled lactate. The ratio of the area under the curve for the summed lactate and pyruvate signals (Lac AUC /Pyr AUC ) was determined to estimate pyruvate-lactate exchange. Data represent mean±SE. Results: 24h exposure to a low concentration of AZD3965 (5nM) led to increased intracellular lactate in MCT4- Raji and MCT4+ Hut78 human lymphoma cells to 2.65-fold and 10-fold respectively (p = ≤0.02) while the effect in MCT4+++ HT29 human colon carcinoma cells was insignificant (167±31% of controls, p = 0.1). Exposure to a high concentration of AZD3965 (500nM) increased intracellular lactate accumulation in HT29 cells albeit to a lesser degree than in Raji and Hut78 cells (4-fold (0.02) vs. 14 to 15-fold (p≤0.01) in the lymphoma lines). This effect is consistent with the expected blockade of lactate release in cells with low or no MCT4 expression following MCT1 inhibition. Lactate build-up in Raji cells was AZD3965 concentration-dependent being observed with as little as 1nM (up 1.7-fold), reaching a maximum at 25nM (12-fold) and plateauing thereafter. Analysis of the hyperpolarized 13 C NMR data showed a significant decrease in Lac AUC /Pyr AUC to 31±6% in 5nM and 19±2% in 25nM AZD3965-treated Raji cells relative to controls (p 13 C-pyruvate being a rate limiting step in the 13 C NMR-observed pyruvate-lactate exchange. Conclusions: Our data show that AZD3965 triggers intracellular lactate accumulation in a concentration- and MCT4 expression-dependent manner and inhibits 13 C-pyruvate-lactate exchange (via blockade of 13 C-pyruvate uptake). Intracellular lactate and hyperpolarized 13 C-pyruvate-lactate exchange measurements are translatable to in vivo imaging studies and are therefore promising non-invasive metabolic biomarkers for AZD3965 and potentially other MCT1 inhibitors. Citation Format: Mounia Beloueche-Babari, Slawomir Wantuch, Markella Koniordou, Harry G. Parkes, Vaitha Arunan, Thomas R. Eykyn, Paul D. Smith, Martin O. Leach. The Monocarboxylate Transporter 1 (MCT1) inhibitor AZD3965 triggers MCT4-dependent lactate accumulation and blocks pyruvate-lactate exchange in human cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C113.