A Cardiac-Specific Robotized Cellular Assay Identified Families of Human Ligands as Inducers of PGC-1α Expression and Mitochondrial Biogenesis.

Abstract : BACKGROUND: Mitochondrial function is dramatically altered in heart failure (HF). This is associated with a decrease in the expression of the transcriptional coactivator PGC-1α, which plays a key role in the coordination of energy metabolism. Identification of compounds able to activate PGC-1α transcription could be of future therapeutic significance. METHODOLOGY/PRINCIPAL FINDINGS: We thus developed a robotized cellular assay to screen molecules in order to identify new activators of PGC-1α in a cardiac-like cell line. This screening assay was based on both the assessment of activity and gene expression of a secreted luciferase under the control of the human PGC-1α promoter, stably expressed in H9c2 cells. We screened part of a library of human endogenous ligands and steroid hormones, B vitamins and fatty acids were identified as activators of PGC-1α expression. The most responsive compounds of these families were then tested for PGC-1α gene expression in adult rat cardiomyocytes. These data highly confirmed the primary screening, and the increase in PGC-1α mRNA correlated with an increase in several downstream markers of mitochondrial biogenesis. Moreover, respiration rates of H9c2 cells treated with these compounds were increased evidencing their effectiveness on mitochondrial biogenesis. CONCLUSIONS/SIGNIFICANCE: Using our cellular reporter assay we could identify three original families, able to activate mitochondrial biogenesis both in cell line and adult cardiomyocytes. This first screening can be extended to chemical libraries in order to increase our knowledge on PGC-1α regulation in the heart and to identify potential therapeutic compounds able to improve mitochondrial function in HF.
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PLoS ONE, Public Library of Science, 2012, 7 (10), pp.e46753. 〈10.1371/journal.pone.0046753〉
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Contributeur : Renée Ventura-Clapier <>
Soumis le : vendredi 14 décembre 2012 - 12:37:03
Dernière modification le : jeudi 11 janvier 2018 - 06:19:00
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Matthieu Ruiz, Delphine Courilleau, Jean-Christophe Jullian, Dominique Fortin, Renée Ventura-Clapier, et al.. A Cardiac-Specific Robotized Cellular Assay Identified Families of Human Ligands as Inducers of PGC-1α Expression and Mitochondrial Biogenesis.. PLoS ONE, Public Library of Science, 2012, 7 (10), pp.e46753. 〈10.1371/journal.pone.0046753〉. 〈inserm-00765218〉

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