Regulation of Monocarboxylate Transporter 1 in Skeletal Muscle Cells by Intracellular Signaling Pathways

Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Biological & Pharmaceutical Bulletin (Impact Factor: 1.83). 01/2010; 33(9):1568-73. DOI: 10.1248/bpb.33.1568
Source: PubMed


Skeletal muscle is the major producer of lactic acid in the body, but its oxidative fibers also use lactic acid as a respiratory fuel. Monocarboxylate transporter (MCT) 1 has been suggested to play a major role in influx of L-lactic acid for oxidation. The regulation mechanism of MCT1 was characterized utilizing rhabdomyosarcoma cells as an in vitro skeletal muscle model. The uptake of L-lactic acid via MCT1 was studied in the presence of various intracellular regulatory pathways, including pathways mediated by protein kinases A, C and G (PKA, PKC and PKG), protein tyrosine kinase (PTK), and Ca2+/calmodulin modulators. The results showed that PKG-, PTK-, and Ca2+/calmodulin-mediated regulatory pathways play no role in the regulation of L-lactic acid uptake, but a role for PKC- and PKA-mediated pathways was apparent. Uptake of L-lactic acid appeared to be stimulated by phorbol 12-myristate 13-acetate (PMA, a PKC activator) via an increase in Vmax of transport processes with no alteration in Km. In parallel, PMA treatment also resulted in an increase in the level of MCT1 expression. On the other hand, exposure to 8-Br-cAMP, a cAMP analog, and to forskolin, an adenylyl cyclase activator, resulted in a significant decrease in L-lactic acid uptake. Additionally, 8-Br-cAMP reduced Vmax but not Km values. Parallel to the decrease in Vmax of L-lactic acid uptake, the level of MCT1 expression was decreased in response to incubation with 8-Br-cAMP. These results indicate the possible involvement of a PKC- and PKA-mediated pathway associated with expression of MCT1 and lactate transport.

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    • "It has been reported that exercise training increases the MCT1 and MCT4 levels in the skeletal and cardiac muscle of humans and animals [66–68]. Although the regulation of MCT expression levels is not clearly understood, it has been suggested that protein kinases A and B are involved in the regulation of MCT expression [69] as an adaptation mechanism, which may be mediated by an increase in lactate movement across the membrane. In addition, our recent study has reported that MCT1 content in erythrocyte membranes is elevated by exercise training in rats [70, 71]. "
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    ABSTRACT: Protons dissociated from organic acids in cells are partly buffered. If not, they are transported to the extracellular fluid through the plasma membrane and buffered in circulation or excreted in urine and expiration gas. Several transporters including monocarboxylate transporters and Na+/H+ exchanger play an important role in uptake and output of protons across plasma membranes in cells of metabolic tissues including skeletal muscle and the liver. They also contribute to maintenance of the physiological pH of body fluid.Therefore, impairment of these transporters causes dysfunction of cells, diseases, and a decrease in physical performance associated with abnormal pH. Additionally, it is known that fluid pH in the interstitial space of metabolic tissues is easily changed due to little pH buffering capacitance in interstitial fluids and a reduction in the interstitial fluid pH may mediate the onset of insulin resistance unlike blood containing pH buffers such as Hb (hemoglobin) and albumin. In contrast, habitual exercise and dietary intervention regulate expression/activity of transporters and maintain body fluid pH, which could partly explain the positive effect of healthy lifestyle on disease prognosis.
    BioMed Research International 07/2014; 2014:598986. DOI:10.1155/2014/598986 · 2.71 Impact Factor
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    • "The molecular mechanisms underlying MCT expression in sarcomas were not under investigation in the present study, however, other studies have addressed this matter using the human rhabdomyosarcoma cell line RD [24,26]. Both MCT1 and MCT4 expressions were shown to be induced by the protein kinase C (PKC) signaling pathway [24,26], while MCT1 expression was shown to be inhibited by PKA signaling pathway [24]. "
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    ABSTRACT: Background Soft tissue sarcomas (STSs) are a group of neoplasms, which, despite current therapeutic advances, still confer a poor outcome to half of the patients. As other solid tumors, STSs exhibit high glucose consumption rates, associated with worse prognosis and therapeutic response. As highly glycolytic tumors, we hypothesized that sarcomas should present an increased expression of lactate transporters (MCTs). Methods Immunohistochemical expression of MCT1, MCT2, MCT4 and CD147 was assessed in a series of 86 STSs and the expression profiles were associated with patients’ clinical-pathological parameters. Results MCT1, MCT4 and CD147 were mainly observed in the plasma membrane of cancer cells (around 60% for MCTs and 40% for CD147), while MCT2 was conspicuously found in the cytoplasm (94.2%). Importantly, we observed MCT1 nuclear expression (32.6%). MCT1 and MCT4, alone or co-expressed with CD147 in the plasma membrane, were associated with poor prognostic variables including high tumor grade, disease progression and shorter overall survival. Conversely, we found MCT1 nuclear expression to be associated with low grade tumors and longer overall survival. Conclusions The present work represents the first report of MCTs characterization in STSs. We showed the original finding of MCT1 expression in the nucleus. Importantly, opposite biological roles should be behind the dual sub-cellular localization of MCT1, as plasma membrane expression of MCT1 is associated with worse patients’ prognosis, while nuclear expression is associated with better prognosis.
    Journal of Translational Medicine 05/2014; 12(1):118. DOI:10.1186/1479-5876-12-118 · 3.93 Impact Factor
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    • " be regulated by PKC ( Narumi et al . 2010 ) . Phorbol 12 - myri - state 13 - acetate , a PKC activator , was shown to increase lactic acid uptake in rhabdomyosarcoma cells as well as to increase MCT1 protein and mRNA levels ( Narumi et al . 2010 ) . In addition , the addition of bisindolylmalei - mide , a PKC inhibitor , abolished these effects ( Narumi et al . 2010 ) . Our findings do not support the role of PKC - h in regulating MCT1 during the onset of skeletal muscle regeneration . Our data demonstrated a decrease in MCT1 protein expression . However , there was a signifi - cant increase in PKC - h protein expression . There are multiple isoforms of PKC and it is possible that MCT1 is being reg"
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    ABSTRACT: The onset of skeletal muscle regeneration is characterized by proliferating myoblasts. Proliferating myoblasts have an increased energy demand and lactate exchange across the sarcolemma can be used to address this increased demand. Monocarboxylate transporters (MCTs) are involved in lactate transport across the sarcolemma and are known to be affected by various physiological stimuli. However, MCT expression at the onset of skeletal muscle regeneration has not been determined. The purpose of this study was to determine if skeletal muscle regeneration altered MCT expression in regenerating tibialis anterior (TA) muscle. Male C57/BL6 mice were randomly assigned to either a control (uninjured) or bupivacaine (injured) group. Three days post injection, the TA was extracted for determination of protein and gene expression. A 21% decrease in muscle mass to tibia length (2.4 ± 0.1 mg/mm vs. 1.9 ± 0.2 mg/mm, P < 0.02) was observed. IGF-1 and MyoD gene expression increased 5.0-fold (P < 0.05) and 3.5-fold (P < 0.05), respectively, 3 days post bupivacaine injection. MCT-1 protein was decreased 32% (P < 0.03); however, MCT-1 gene expression was not altered. There was no difference in MCT4 protein or gene expression. Lactate dehydrogenase (LDH)-A protein expression increased 71% (P < 0.0004). Protein levels of LDH-B and mitochondrial enzyme cytochrome C oxidase subunit decreased 3 days post bupivacaine injection. CD147 and PKC-θ protein increased 64% (P < 0.03) and 79% (P < 0.02), respectively. MCT1 but not MCT4 expression is altered at the onset of skeletal muscle regeneration possibly in an attempt to regulate lactate uptake and use by skeletal muscle cells.
    09/2013; 1(4):e00075. DOI:10.1002/phy2.75
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