title: Combined pharmacological activation of AMPK and PPARδ potentiates the effects of exercise in trained mice.
abstract: The combined activation of the cellular energy sensor AMP-activated protein kinase (AMPK) and the nuclear transcription factor peroxisome proliferator-activated receptor delta (PPARδ) has been demonstrated to improve endurance and muscle function by mimicking the effects of exercise training. However, their combined pharmacological activation with exercise training has not been explored. Balb/c mice were trained on a treadmill and administered both the AMPK activator AICAR and the PPARδ agonist GW0742 for 4 weeks. AICAR treatment potentiated endurance, but the combination of AICAR and GW0742 further potentiated endurance and increased all running parameters significantly relative to exercised and nonexercised groups (138-179% and 355% increase in running time, respectively). Despite the lack of change in basal whole-body metabolism, a significant shift to fat as the main energy source with a decline in carbohydrate utilization was observed upon indirect calorimetry analysis at the period near exhaustion. Increased energy substrates before exercise, and elevated muscle nonesterified fatty acids (NEFA) and elevated muscle glycogen at exhaustion were observed together with increased PDK4 mRNA expression. Citrate synthase activity was elevated in AICAR-treated groups, while PGC-1α protein level tended to be increased in GW0742-treated groups. At exhaustion, Pgc1a was robustly upregulated together with Pdk4, Cd36, and Lpl in the muscle. A robust upregulation of Pgc1a and a downregulation in Chrebp were observed in the liver. Our data show that combined pharmacological activation of AMPK and PPARδ potentiates endurance in trained mice by transcriptional changes in muscle and liver, increased available energy substrates, delayed hypoglycemia through glycogen sparing accompanied by increased NEFA availability, and improved substrate shift from carbohydrate to fat.
authors.affiliation: Graduate School of Agriculture, Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Kyoto University, Kyoto, Japan.
authors.forename: Mark Christian C
authors.initials: MC
authors.lastname: Manio
authors.affiliation: Graduate School of Agriculture, Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Kyoto University, Kyoto, Japan ashlaoh@kyoto-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Graduate School of Agriculture, Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Kyoto University, Kyoto, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Fujitani
authors.affiliation: Graduate School of Agriculture, Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Kyoto University, Kyoto, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Graduate School of Agriculture, Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Kyoto University, Kyoto, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fushiki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002151:Calorimetry / Q000379:methods; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D010805:Physical Conditioning, Animal / Q000379:methods / Q000502:physiology*; D010807:Physical Endurance / Q000187:drug effects / Q000502:physiology; D012265:Ribonucleotides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D047494:PPAR delta; D012265:Ribonucleotides; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C031143:AICA ribonucleotide
keywords: AMPK and PPAR delta; endurance exercise; gene expression; metabolism; substrate shift