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PGC1 Encoded by the PPARGC1A Gene Regulates Oxidative Energy Metabolism in Equine Skeletal Muscle During Exercise

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PGC1 Encoded by the PPARGC1A Gene Regulates Oxidative Energy Metabolism in Equine Skeletal Muscle During Exercise 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 (T0), immediately post-exercise (T1) and 4 h post-exercise (T2). Significant (P < 0.05) expression fold change differences relative to T0 were detected for genes functioning in angiogenesis (ANGP2 and VEGFA); Ca2+-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. receptor-c coactivator-1a (PGC-1a) has emerged as a fun- Introduction damental turning point in understanding the molecular Skeletal muscle has a remarkable ability to respond to the contributions leading to exercise-induced phenotypic adap- metabolic stresses imposed by physical activity. The meta- tations in mammalian skeletal muscle, including oxidative bolic demand for fuel in response to exercise in skeletal phosphorylation, mitochondrial biogenesis, muscle fibre- muscle is limited by ATP availability, activity of oxidative type switching and angiogenesis (Handschin et al. 2003; enzymes, the availability of oxygen, and mitochondrial Arany 2008). Exercise is a powerful inducer of PPARGC1A content. The discovery of peroxisome proliferator-activated gene and PGC-1a protein expression in human and mouse skeletal muscle (Pilegaard et al. 2003; Russell et al. 2005; Address for correspondence Wende et al. 2005). During exercise, a number of signalling pathways are Emmeline W. Hill, Animal Genomics Laboratory, UCD School of Agriculture, Food Science and Veterinary Medicine, UCD College of activated that have been identified as key regulators of PGC- Life Sciences, University College Dublin, Belfield, Dublin 4, Ireland. 1a activity and function. The calcineurin (Handschin et al. E-mail: [email protected] 2003), p38 mitogen-activated protein kinase (MAPK) Accepted for publication 28 March 2011 (Akimoto et al. 2005) and adenosine monophosphate Ó 2011 The Authors, Animal Genetics Ó 2011 Stichting International Foundation for Animal Genetics, 43, 153–162 153 154 Eivers et al. (AMP)-activated protein kinase (AMPK) (Jager et al. 2007) Children (Ireland), and ownersÕ consent was obtained for all signalling pathways influence PGC-1a activity directly or horses. via PGC-1a coactivation. PGC-1a is a powerful activator of a number of different transcriptional coactivators, such as Subjects nuclear respiratory factor 1 and 2 (NRF-1 and NRF2). These proteins bind to and interact with a number of mitochon- The study cohort comprised eight 4-year-old untrained drial genes in the cell nucleus, resulting in increased mito- Thoroughbred horses (castrated males) raised at the same chondrial biogenesis (Lin et al. 2005). Regulation of farm for the previous 12 months and destined for National mitochondrial fatty acid oxidation occurs via PGC-1a Hunt racing with the same trainer. The horses had a mean interaction with peroxisome proliferator-activated receptor (±SD) height of 165.25 ± 1.44 cm and a mean pre-exercise alpha. In addition, PGC-1a has been shown to influence weight of 565.75 ± 13.71 kg. control of fatty acid oxidation via PDK4 by its interaction Details on subject physiological and biochemical charac- with oestrogen-related receptor alpha (ERRa) (Zhang et al. teristics are presented in Table 1. 2006; Wende et al. 2005). The forkhead transcription fac- tor FOXO1 also directly regulates PDK4 through binding Exercise protocol sites in the PDK4 gene promoter region (Kwon et al. 2004; Lin et al. 2005). The eight untrained Thoroughbred horses participated in a Aside from its regulatory role in fatty acid metabolism standardized incremental-step exercise test (Rose et al. and mitochondrial function, Arany et al. (2008) have 1990, 1990; Woodie et al. 2005) on a high-speed equine identified PGC-1a as a major regulator of angiogenesis treadmill (Sato; Sato AB). The treadmill was set to a 6° through coactivation of ERRa under pathologic ischaemia incline. The warm-up consisted of 2 min at 2 m/s, followed in addition to physiological conditions such as exercise by 2 min at 4 m/s and 2 min at 6 m/s. Warm-up was fol- (Hudlicka et al. 1992). In addition to the role of PGC-1a in lowed by an increase in treadmill velocity to 9 m/s for 60 s mitochondrial biogenesis and fatty acid oxidation, it also and then a 1 m/s increase in treadmill velocity every 60 s functions to regulate muscle fibre-type switching via tran- until the animal was no longer able to maintain its position scriptional coactivation of the myocyte enhancer factor 2 on the treadmill at that speed or until the heart rate reached gene family (MEF2A, MEF2B, MEF2C and MEF2D), a plateau (HRmax). Heart rate was measured continuously inducing a fast-to-slow fibre-type switch (Wu et al. 2001). before, during and after exercise by telemetry (Polar Equine In a previous study, we observed the activation of the S810i heart rate monitor system; Polar Electro Ltd). Fol- pAMPKa and PGC-1a proteins in Thoroughbred horse lowing warm-up, the exercise test comprised an average of skeletal muscle following a single bout of exercise (Eivers six (range 5–7) incremental steps achieving a mean maxi- et al. 2009). Furthermore, we reported a significant increase mum velocity of 12.4 ± 0.2 m/s and a mean distance of in expression of the gene encoding PGC-1a (PPARGC1A). 4362.9 ± 102.7 m for an average duration of 8.77 ± The PGC-1a response and interaction with molecular sig- 0.5 min. Details on exercise parameters are presented in nalling pathways in the phenotypic adaptation of equine Table 1. skeletal muscle to exercise has not previously been reported. However, it is well established that PGC-1a plays a pivotal role in energy metabolism and resistance to fatigue in hu- Table 1 Exercise test details. mans and rodents. There have been numerous reports in Mean SD (±) the literature describing the effects of exercise on PPARG- C1A gene expression in these species (Pilegaard et al. 2003; Resting HR (bpm) 32.63 1.42 Maximum HR (bpm) 217.50 3.32 McGee & Hargreaves 2004; Akimoto et al. 2005; Russell Velocity at maximum HR (m/s) 12.43 0.24 et al. 2005; Vissing et al. 2005; Wright et al. 2007). Distance of treadmill exercise (m) 4362.87 102.71 Therefore, the purpose of the present study was to evaluate Pre-exercise muscle biopsy T0 1:19 0.03 the hypothesis that a single bout of exercise in Thorough- (hours–minutes pre-exercise) bred horses leads to changes in mRNA expression for genes Post-exercise muscle biopsy T1 6:46 0.07 encoding transcriptional coactivators of PGC-1a and genes (minutes–seconds post-exercise) that function upstream and downstream of PGC-1a in Post-exercise muscle biopsy T2 4:14 0.02 known canonical pathways. (hours–minutes post-exercise) An incremental-step exercise test to maximum HR was performed for Materials and methods n = 8 subjects. The mean distance of the exercise tests was 4.4 km. Skeletal muscle biopsy samples were collected before exercise (T0), All animal procedures were approved by the University immediately post-exercise (T1) and 4 h post-exercise (T2), for gene College Dublin, Animal Research Ethics Committee; a expression analyses. licence was granted from the Department of Health and HR, heart rate. Ó 2011 The Authors, Animal Genetics Ó 2011 Stichting International Foundation for Animal Genetics, 43, 153–162 PGC-1a a key regulator of oxidative energy metabolism 155 Muscle biopsy sampling MassARRAYÒ Quantitative Gene Expression (QGE) analysis Percutaneous needle muscle biopsies (Lindholm & Piehl 1974) were obtained from the dorsal compartment of the Real-time competitive PCR coupled with product resolution gluteus medius muscle according to the methods of via matrix-assisted laser desorption/ionization time-of-flight Dingboom et al. (1999) using a 6-mm-diameter, modified (MALDI-TOF) mass spectrometry (MassARRAYÒ QGE; Bergstrom biopsy needle (Jørgen KRUUSE, Veterinary Sequenom) was performed as previously described (Ding & Supplies). Biopsy samples were preserved in RNAlaterÒ Cantor 2003) in order to estimate copy number values for (Ambion/Applied Biosystems).
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