doi:10.1111/j.1365-2052.2011.02238.x PGC-1a encoded by the PPARGC1A gene regulates oxidative energy metabolism in equine skeletal muscle during exercise S. S. Eivers*, B. A. McGivney*, J. Gu*, D. E. MacHugh* ,† , L. M. Katz ‡ and E. W. Hill* *Animal Genomics Laboratory, UCD School of Agriculture, Food Science and Veterinary Medicine, UCD College of Life Sciences, University College Dublin, Belfield, Dublin 4, Ireland. † UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. ‡ University Veterinary Hospital, UCD School of Agriculture, Food Science and Veterinary Medicine, UCD College of Life Sciences, University College Dublin, Belfield, Dublin 4, Ireland Summary Peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a) has emerged as a critical control factor in skeletal muscle adaptation to exercise, acting via transcriptional control of genes responsible for angiogenesis, fatty acid oxidation, oxidative phosphoryla- tion, mitochondrial biogenesis and muscle fibre type composition. In a previous study, we demonstrated a significant increase in mRNA expression for the gene encoding PGC-1a (PPARGC1A) in Thoroughbred horse skeletal muscle following a single bout of endurance exercise. In this study, we investigated mRNA expression changes in genes encoding transcriptional coactivators of PGC-1a and genes that function upstream and downstream of PGC-1a in known canonical pathways. We used linear regression to determine the associations between PPARGC1A mRNA expression and expression of the selected panel of genes. Biopsy samples were obtained from the gluteus medius pre-exercise (T 0 ), immediately post-exercise (T 1 ) and 4 h post-exercise (T 2 ). Significant (P < 0.05) expression fold change differences relative to T 0 were detected for genes functioning in angiogenesis (ANGP2 and VEGFA); Ca 2+ -dependent signalling pathway (PPP3CA); carbohydrate/glucose metabolism (PDK4); fatty acid metabolism/mitochondrial biogenesis (PPPARGC1B); haem biosynthetic process (ALAS1); insulin signalling (FOXO1, PPPARGC1A and SLC2A4); mitogen-activated protein kinase signalling (MAPK14 and MEF2A); and myogenesis (HDAC9). Gene expres- sion associations were identified between PPARGC1A and genes involved in angiogenesis, mitochondrial respiration, glucose transport, insulin signalling and transcriptional regu- lation. These results suggest that PGC-1a and genes regulated by PGC-1a play significant roles in the skeletal muscle response to exercise and therefore may contribute to perfor- mance potential in Thoroughbred horses. Keywords athletic performance, gene expression, PGC-1a, thoroughbred. Introduction Skeletal muscle has a remarkable ability to respond to the metabolic stresses imposed by physical activity. The meta- bolic demand for fuel in response to exercise in skeletal muscle is limited by ATP availability, activity of oxidative enzymes, the availability of oxygen, and mitochondrial content. The discovery of peroxisome proliferator-activated receptor-c coactivator-1a (PGC-1a) has emerged as a fun- damental turning point in understanding the molecular contributions leading to exercise-induced phenotypic adap- tations in mammalian skeletal muscle, including oxidative phosphorylation, mitochondrial biogenesis, muscle fibre- type switching and angiogenesis (Handschin et al. 2003; Arany 2008). Exercise is a powerful inducer of PPARGC1A gene and PGC-1a protein expression in human and mouse skeletal muscle (Pilegaard et al. 2003; Russell et al. 2005; Wende et al. 2005). During exercise, a number of signalling pathways are activated that have been identified as key regulators of PGC- 1a activity and function. The calcineurin (Handschin et al. 2003), p38 mitogen-activated protein kinase (MAPK) (Akimoto et al. 2005) and adenosine monophosphate Address for correspondence Emmeline W. Hill, Animal Genomics Laboratory, UCD School of Agriculture, Food Science and Veterinary Medicine, UCD College of Life Sciences, University College Dublin, Belfield, Dublin 4, Ireland. E-mail: emmeline.hill@ucd.ie Accepted for publication 28 March 2011 Ó 2011 The Authors, Animal Genetics Ó 2011 Stichting International Foundation for Animal Genetics, 43, 153–162 153