No abstract

Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPAR␥ coactivator (PGC)-1␣ is a potent transcriptional coactivator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1␣ mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1␣ in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1␣ from an alternate promoter. The induction of PGC-1␣ depended on ␤-adrenergic signaling. ␤-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1␣. The orphan nuclear receptor ERR␣ mediated the induction of VEGF by PGC-1␣, and mice lacking ERR␣ also failed to increase vascular density after exercise. These data demonstrate that ␤-adrenergic stimulation of a PGC-1␣/ERR␣/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.VEGF ͉ ERR␣ ͉ ␤-adrenergic

The transcriptional coactivator PGC-1␣ 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␣ 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␣ 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␣ mRNA, and the expression of a number of genes known to be regulated by PGC-1␣. No induction of these target genes is seen in PGC-1␣ ؊/؊ cells, demonstrating that the drugs act through PGC-1␣. These data demonstrate the feasibility of high-throughput screening for inducers of PGC-1␣. Moreover, the data identify microtubule inhibitors and protein synthesis inhibitors as modulators of PGC-1␣ and oxidative phosphorylation.colchicine ͉ high throughput C oactivators are proteins that dock on transcription factors and alter chromatin structure and the transcription machinery to stimulate gene expression (reviewed in ref.