A metabolomic study of the PPARδ agonist GW501516 for enhancing running endurance in Kunming mice

Abstract

Exercise can increase peroxisome proliferator-activated receptor-δ (PPARδ) expression in skeletal muscle. PPARδ regulates muscle metabolism and reprograms muscle fibre types to enhance running endurance. This study utilized metabolomic profiling to examine the effects of GW501516, a PPARδ agonist, on running endurance in mice. While training alone increased the exhaustive running performance, GW501516 treatment enhanced running endurance and the proportion of succinate dehydrogenase (SDH)-positive muscle fibres in both trained and untrained mice. Furthermore, increased levels of intermediate metabolites and key enzymes in fatty acid oxidation pathways were observed following training and/or treatment. Training alone increased serum inositol, glucogenic amino acids, and branch chain amino acids. However, GW501516 increased serum galactose and β-hydroxybutyrate, independent of training. Additionally, GW501516 alone raised serum unsaturated fatty acid levels, especially polyunsaturated fatty acids, but levels increased even more when combined with training. These findings suggest that mechanisms behind enhanced running capacity are not identical for GW501516 and training. Training increases energy availability by promoting catabolism of proteins, and gluconeogenesis, whereas GW501516 enhances specific consumption of fatty acids and reducing glucose utilization.

α‐Lipoic acid up‐regulates expression of peroxisome proliferator‐activated receptor b in skeletal muscle: involvement of the JNK signaling pathway

“…It is tempting to say that α‐LA and exercise training exert similar effects on skeletal muscle PPARβ expression. PPARβ expression is higher in trained mice skeletal muscle than in their sedentary counterparts, probably explaining why agonist GW1516 increases endurance treadmill running performance in some studies (18, 30). Other studies report, in insulin‐resistant animals, an additive effect of α‐LA treatment and endurance exercise, characterized by a greater improvement in insulin action and glucose transport (31, 32).…”

Exercise in a Pill: The Latest on Exercise-Mimetics

“…These new data highlight the possibility that exercise and GW501516 exert beneficial effects through two different mechanisms. Although both treatments increased mitochondrial fatty acid oxidation and fat metabolism in skeletal muscle, exercise acts by promoting catabolism, glycolysis and gluconeogenesis, while GW501516 regulates branched chain amino acid and ketone body pathways [ 80 ]. It is also worth mentioning that another PPAR δ activator, GW0742, recently administered for 4 weeks in combination with AICAR (5 mg/kg and 500 mg/kg, respectively) to 7-week-old male Balb/c mice, increased running both in training and sedentary cohorts (138–179% and 355% increase), along with a shift to fat as main energy source [ 82 ].…”

Annual banned‐substance review: analytical approaches in human sports drug testing

“…These exercise‐mimetic properties however did not translate to positive effects on the brain that are commonly observed with sport practice, but enhanced insulin signaling in skeletal muscle tissue was found, at least partially attributed to the downregulation of the microRNA‐29 . The performance‐enhancing effects of the PPARδ agonist GW1516 (or GW501516) were investigated using metabolomics approaches, and a variety of factors including the proportion of succinate dehydrogenase‐positive muscle fibers, serum galactose, β‐hydroxybutyrate, and unsaturated fatty acid levels were found to change significantly in mice studied under the influence of the discontinued drug candidate . Since these alterations were complementary to exercise‐induced changes, distinct mechanisms for training and drug‐derived performance enhancements were suggested.…”

“…[175] The performance-enhancing effects of the PPARδ agonist GW1516 (or GW501516) were investigated using metabolomics approaches, and a variety of factors including the proportion of succinate dehydrogenase-positive muscle fibers, serum galactose, β-hydroxybutyrate, and unsaturated fatty acid levels were found to change significantly in mice studied under the influence of the discontinued drug candidate. [176] Since these alterations were complementary to exercise-induced changes, distinct mechanisms for training and drug-derived performance enhancements were suggested.…”