Combined pharmacological activation of AMPK and PPARδpotentiates 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 (PPAR δ) 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 PPAR δ 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 PPAR δ 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.

Chronic 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Treatment Induces Phenotypic Changes in Skeletal Muscle, but Does Not Improve Disease Outcomes in the R6/2 Mouse Model of Huntington’s Disease

“…However, the increased expression of AMPK in AICAR-treated WT and R6/2 mice negated a potential increase in the ratio of p-AMPK to AMPK in these groups (Figures 1 A,B). This is consistent with previous reports showing modest effects of AICAR on AMPK phosphorylation in muscle following chronic administration ( 55 , 56 ), a phenomenon likely caused by habituation. Of relevance, we did not observe an effect of genotype in either AMPK or p-AMPK protein content in muscle from WT and R6/2 animals following AICAR administration, indicating that HD mice responded to treatment similarly to WT animals.…”

CD36 is essential for endurance improvement, changes in whole-body metabolism, and efficient PPAR-related transcriptional responses in the muscle with exercise training

“…Basal indirect calorimetry was performed according to Manio et al. (). Mice were placed individually in acrylic chambers from the 3rd day before the last training session.…”

“…Lipids were extracted from powdered muscle samples as described in Manio et al. () with some modifications. Approximately 30 mg samples were mixed thoroughly with 1 mL Folch reagent.…”

“…Citrate synthase (CS) activity was measured based on Manio et al. () and Srere (). Protein concentration of the final adjusted lysate was used in all the calculations.…”

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

“…Indeed, numerous studies have shown that PPAR β / δ overexpression or activation in muscle dramatically improves FA utilization as energy source, reduces hyperlipidemia, improves endurance, and decreases insulin secretion from β -cells [32, 35–37]. …”