A cardiac-specific robotized cellular assay identified families of human ligands as inducers of PGC-1α expression and mitochondrial biogenesis.
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.


RESULTS
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
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.
INSERM, U-769, Univ Paris-Sud, Châtenay-Malabry, France.
Matthieu
M
Ruiz
Delphine
D
Courilleau
Jean-Christophe
JC
Jullian
Dominique
D
Fortin
Renée
R
Ventura-Clapier
Jean-Paul
JP
Blondeau
Anne
A
Garnier
D000818:Animals; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D063269:Mitochondrial Turnover / Q000235:genetics / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014803:Vitamin B Complex / Q000378:metabolism
D005227:Fatty Acids; D012739:Gonadal Steroid Hormones; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D014803:Vitamin B Complex