A cardiac-specific robotized cellular assay identified families of human ligands as inducers of PGC-1alpha expression and mitochondrial biogenesis.
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Ruiz M, Courilleau D, Jullian JC, Fortin D, Ventura-Clapier R, Blondeau JP, Garnier A
A cardiac-specific robotized cellular assay identified families of human ligands as inducers of PGC-1alpha expression and mitochondrial biogenesis.
PLoS One. 2012;7(10):e46753. doi: 10.1371/journal.pone.0046753. Epub 2012 Oct 3.
- PubMed ID
- 23056435 [ View in PubMed]
- 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-1alpha, which plays a key role in the coordination of energy metabolism. Identification of compounds able to activate PGC-1alpha 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-1alpha 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-1alpha 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-1alpha expression. The most responsive compounds of these families were then tested for PGC-1alpha gene expression in adult rat cardiomyocytes. These data highly confirmed the primary screening, and the increase in PGC-1alpha 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-1alpha regulation in the heart and to identify potential therapeutic compounds able to improve mitochondrial function in HF.