Gene expression-based screening identifies microtubule inhibitors as inducers of PGC-1alpha and oxidative phosphorylation.
The transcriptional coactivator PGC-1alpha 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-1alpha 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-1alpha expression in skeletal muscle cells. A number of drug classes are identified, including glucocorticoids, microtubule inhibitors, and protein synthesis inhibitors. These drugs induce PGC-1alpha mRNA, and the expression of a number of genes known to be regulated by PGC-1alpha. No induction of these target genes is seen in PGC-1alpha -/- cells, demonstrating that the drugs act through PGC-1alpha. These data demonstrate the feasibility of high-throughput screening for inducers of PGC-1alpha. Moreover, the data identify microtubule inhibitors and protein synthesis inhibitors as modulators of PGC-1alpha and oxidative phosphorylation.
Arany
Zoltan
Z
Dana Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Wagner
Bridget K
BK
Ma
Yanhong
Y
Chinsomboon
Jessica
J
Laznik
Dina
D
Spiegelman
Bruce M
BM
D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D050257:Tubulin Modulators / Q000032:analysis* / Q000494:pharmacology*
D005938:Glucocorticoids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D050257:Tubulin Modulators