Peroxisome Proliferator-Activated Receptor -beta/delta, -gamma Agonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism

PPAR-alpha, PPAR-beta, and PPAR-gamma, and RXR in conjunction with PGC-1 alpha and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12 muscle myoblasts displayed a reduction of PGC-1 alpha, PPAR-alpha, and RXR-alpha mRNA, as well as CPT-1b and UCP-2mRNA. SIRT1 and PGC-1 alpha protein was reduced, and PPAR-gamma protein increased. The addition of a PPAR-beta agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1 alpha, RXR-alpha, PPAR-alpha, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-alpha, PPAR-alpha mRNA, and PPAR-gamma and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.