Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1α and oxidative phosphorylation

The transcriptional coactivator PGC-1 alpha is a potent regulator of several metabolic pathways, including, in particular, the activation of oxidative phosphorylation and mitochondrial biogenesis. Recent evidence suggests that increasing PGC-1 alpha activity may have beneficial effects in various conditions, including muscular dystrophy, diabetes, and neurodegenerative diseases. We describe here a high-throughput screen to identify small molecules that induce PGC-1 alpha expression in skeletal muscle cells. A number of drug classes are identified, including glucocorticoids, microtubule inhibitors, and protein synthesis inhibitors. These drugs induce PGC-1 alpha mRNA, and the expression of a number of genes known to be regulated by PGC-1 alpha. No induction of these target genes is seen in PGC-1 alpha -/- cells, demonstrating that the drugs act through PGC-1 alpha. These data demonstrate the feasibility of high-throughput screening for inducers of PGC-1 alpha. Moreover, the data identify microtubule inhibitors and protein synthesis inhibitors as modulators of PGC-1 alpha and oxidative phosphorylation.