One of the benefits to fitness derived from regular exercise is enhanced circulation in the limbs. On the flip side, a sedentary lifestyle is a major factor in the genesis of peripheral artery disease. Chinsomboon et al. explored a signaling pathway by which exercise promotes generation of new blood vessels in muscle. They focused on PGC-1α (PPARγ coactivator 1α), which promotes angiogenesis in muscle. PGC-1α is so named because it acts as a transcriptional coactivator with the nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), which regulate lipid and glucose metabolism. Mice provided with a running wheel will do some serious voluntary endurance training, running as much as 8 kilometers a day. Such exercise was correlated with increased vascularization of the quadriceps muscle. However, in mice genetically engineered to lack expression of PGC-1α in muscle, the beneficial effect of exercise on angiogenesis was nearly absent. The PGC-1α gene has an alternative promoter upstream of the proximal promoter that results in a slightly different PGC-1α protein with a few extra N-terminal amino acids. Expression of mRNA from this promoter was enhanced 100-fold after exercise, whereas the transcription from the proximal promoter remained the same. It is not clear whether the slight alteration of the protein affects its function or whether the alternative promoter (found only in muscle and adipose tissue) serves primarily to confer tissue-specific regulation. Signaling by β-adrenergic receptors increases expression of PGC-1α mRNA, and pharmacological inhibition of such signaling prevented most of the effect of exercise on expression of PGC-1α. Treatment of animals with a β-adrenergic receptor agonist also promoted expression of vascular endothelial growth factor (VEGF), an important component of the angiogenic response, and this effect was blocked in the animals lacking PGC-1α in muscle tissue. PGC-1α works together with the nuclear receptor estrogen-related receptor α (ERRα) to regulate expression of the VEGF gene, and in ERR–/– mice, exercise failed to induce angiogenesis. The authors thus propose that an exercise-induced increase in β-adrenergic signaling promotes expression of PGC-1α through a cyclic adenosine monophosphate (cAMP) response element in its alternative promoter. PGC-1α then works with ERRα to increase production of VEGF and promote angiogenesis. This is likely not the only pathway at work, but the authors note that it is independent of hypoxia-induced signaling or metabolic sensing by the AMP-activated protein kinase, two mechanisms proposed earlier but lacking in strong experimental support. Clinical implications include the possibility that the pathway could be targeted for therapies aimed at increasing vascularity and the cautionary note that antagonist of β-adrenergic signaling commonly prescribed for patients with coronary artery disease may have the unwanted side effect of inhibiting one of the beneficial effects of exercise in those patients.
J. Chinsomboon, J. Ruas, R. K. Gupta, R. Thom, J. Shoag, G. C. Rowe, N. Sawada, S. Raghuram, Z. Arany, The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle. Proc. Natl. Acad. Sci. U.S.A. 106, 21401–21406 (2009). [Abstract][Full Text]