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Metabolic alterations derived from absence of Two-Pore Channel 1 at cardiac level

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Abstract

Two-pore channels (TPCs or TPCNs) are novel voltage-gated ion channels that have been postulated to act as Ca2+ and/or Na+ channels expressed exclusively in acidic organelles such as endosomes and lysosomes. TPCNs participate in the regulation of diverse biological processes and recently have been proposed to be involved in the pathophysiology of metabolic disorders such as obesity, fatty liver disease and type 2 diabetes mellitus. Due to the importance of these pathologies in the development of cardiovascular diseases, we aimed to study the possible role of two-pore channel 1 (TPCN1) in the regulation of cardiac metabolism. To explore the cardiac function of TPCN1, we developed proteomic approaches as 2-DE-MALDI-MS and LC-MALDI-MS in the cardiac left ventricle of TPCN1 KO and WT mice, and found alterations in several proteins implicated in glucose and fatty acid metabolism in TPCN1 KO vs. WT mice. The results confirmed the altered expression of HFABP, a key fatty acid transport protein, and of enolase and PGK1, the key enzymes in the glycolytic process. Finally, in vitro experiments performed in neonatal rat cardiomyocytes, in which TPCN1 was silenced using siRNAs, confirmed that the downregulation of TPCN1 gene expression increased 2-deoxy-D-[3H]-glucose uptake and GLUT4 mobilization into cell peripherals in cardiac cells. Our results are the first to suggest a potential role for TPCNs in cardiac metabolism regulation.

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Acknowledgements

Funding was from the cardiovascular research network (RIC) of the Spanish thematic cooperative research networks in health (RETICs) associated with the Carlos III Health Institute and European Regional Development Fund (ERDF). The funding source was not involved in the conduct of the research and/or preparation of the article, or in the decision to submit the article for publication.

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    Authors and Affiliations

    1. Cellular and Molecular Cardiology Research Unit and Department of Cardiology,, Institute of Biomedical Research and University Clinical Hospital, 15706, Santiago de Compostela, Spain

      Vanessa García-Rúa, Sandra Feijóo-Bandín, María García-Vence, Alana Aragón-Herrera, Diego Rodríguez-Penas, Ana Mosquera-Leal, José Ramón González-Juanatey & Francisca Lago

    2. Laboratory of Proteomics, Institute of Biomedical Research and University Clinical Hospital, 15706, Santiago de Compostela, Spain

      Susana B Bravo & Jana Alonso

    3. Department of Pharmacology, University of Oxford, Oxford, UK

      Pamela V Lear & John Parrington

    4. La Fe University Hospital, 46026, Valencia, Spain

      Esther Roselló-Lletí, Manuel Portolés & Miguel Rivera

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    1. Vanessa García-Rúa
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    Correspondence to Sandra Feijóo-Bandín.

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    [García-Rúa V, Feijóo-Bandín S, García-Vence M, Aragón-Herrera A, Bravo SB, Rodríguez-Penas D, Mosquera-Leal A, Lear PV, Parrington J, Alonso J, Roselló-Lletí E, Portolés M, Rivera M, González-Juanatey JR and Lago F 2016 Metabolic alterations derived from the absence of Two-Pore Channel 1 (TPCN1) at cardiac level. J. Biosci.]

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    Vanessa García-Rúa, Sandra Feijóo-Bandín and María García-Vence contributed equally to this work.

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    García-Rúa, V., Feijóo-Bandín, S., García-Vence, M. et al. Metabolic alterations derived from absence of Two-Pore Channel 1 at cardiac level. J Biosci 41, 643–658 (2016). https://doi.org/10.1007/s12038-016-9647-4

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