In a 2017 study, researchers sought to determine the role of the peroxisome proliferator-activated receptor delta (PPAR-delta) cell signaling pathway in exercise-induced improvements in endurance. The researchers found PPAR-delta improves endurance by reducing glucose release and metabolism and increasing fat metabolism in muscle tissue.
Exercise is believed to improve endurance by reducing the extent to which the body is dependent upon the simple sugar glucose for energy. The transition skeletal muscle fibres undergo, from dominantly glycolytic (glucose-fueled, fatigue-susceptible) to dominantly oxidative (fat-fueled, fatigue-resistant), is well established. The contribution of altered fat and glucose metabolism to exercise-induced improvements in endurance and the cellular pathways involved, however, are not fully understood. An improved understanding of the mechanisms which underlie muscle metabolism and endurance may lead to the development of more effective therapies for muscular and metabolic diseases, and help speed recovery after injury.
In a 2017 study published in Cell Metabolism, researchers explored the effect of the peroxisome proliferator-activated receptor delta (PPAR-delta) cellular pathway – associated with increased breakdown of fats in skeletal muscle tissue and with transition from glycolytic to oxidative muscle fibres – on running endurance and glucose and fat metabolism.
Two sets of endurance experiments were performed. In the first set, male mice aged 2-4 months with active (wild-type) and inactive (PD-KO) PPAR-delta cellular pathways were used to evaluate training-related changes in endurance. Mice were assigned to receive (active) or not to receive (sedentary) treadmill training. Active mice were familiarized with running on a rodent treadmill at gradually increasing speeds of 5-10 m/min, 3 days per week. They were then trained daily for 4 weeks, running for 1 hour at 10 m/min. Both active and sedentary mice then performed run-to-exhaustion tests, in which speed was gradually increased from 10 to 15 m/min within the first 10 minutes, and mice ran as long as they could at 15 m/min. In the second set, sedentary wildtype and PD-KO mice were assigned to receive food containing (GW+) or not containing (GW-) 40 mg/kg of the PPAR-delta pathway activator GW501516 for 8 weeks and then given exhaustion tests. The effect of glucose supplementation after exhaustion in GW+ and GW- mice was also tested. For both sets, blood samples were collected, levels of activity and heart rates were recorded, and breathing was monitored during testing. After experiments the mice were euthanized, quadriceps muscles were dissected and weighed, and the cellular contents of their quadriceps muscles were analyzed.
Blood and cell samples were analyzed for levels of lactate, indicative of the release of glucose from its stored form, glycogen; glucose; palmitoyl-carnitine (cpt1b), which promotes fat breakdown; pyruvate dehydrogenase kinase four (pdk4), which prevents glucose breakdown; PPAR-delta; and succinate, indicative of any cellular metabolism. Using a ventilometer and heart monitor, oxygen consumption (VO2), indicative of energy expenditure; the respiratory exchange rate (RER), the ratio of carbon dioxide produced to oxygen consumed; and movements per hour were measured. The rate of oxygen consumption with respect to palmitate production (OCR), indicative of fat metabolism, was also used as a measure of energy expenditure.
For training-related endurance experiments, active wildtype mice had decreased RERs and increased VO2s over 48 hours compared to sedentary wildtype mice, suggesting a switch from glycolytic to oxidative metabolism with training. RERs and VO2s did not differ significantly between active and sedentary PD-KO mice. On exhaustion tests, the length of time spent running beyond 1 hour was twice as long for wildtype mice compared to PD-KO mice. Levels of pdk4 were higher in active mice than in sedentary mice, and in wildtype more than PD-KO mice. Levels of cpt1b were only increased in active wildtype mice. Lactate levels were inversely proportionate to pdk4 and cpt1b levels. In active mice, PPAR-delta levels increased with the distance run, activity, and gastrocnemius mass. In sedentary mice, there was no correlation found between PPAR-delta levels and VO2, RER, or OCR, suggesting the PPAR-delta pathway is not normally active in the absence of habitual exercise.
Sedentary GW+ wildtype mice had RERs comparable to those of active wildtype mice, suggesting increased fat metabolism. OCRs were also 50% higher in GW+ wildtype mice compared to other mice, though succinate levels did not change. GW+ wildtype mice had far greater levels of pdk4 and cpt1b, but 40% lower levels of lactate, suggesting PPAR-delta may suppress the release of glucose release from glycogen. GW+ wildtype mice ran for 1.5 hours longer on exhaustion tests than their GW- counterparts. Injection with 250 mg/kg of glucose extended the running times of exhausted mice by approximately 20 minutes. Blood glucose levels dropped in GW- mice after 90-120 minutes, but after 180 minutes for GW+ mice.
Fibre type in the quadriceps muscles transitioned from glycolytic to oxidative in both active wildtype and active PD-KO mice, but was not significantly altered in GW+ sedentary mice, suggesting PPAR-delta is not itself sufficient to induce this switch and that its effects on metabolism are independent of fibre type.
Overall, the study findings suggest that PPAR-delta improves endurance by reducing glucose release and breakdown and increasing fat metabolism in muscle tissue. Moreover, these effects appear to be independent of exercise-induced changes in muscle fibre type. The additional 4 weeks of GW treatment may, in part, account for the greater effects observed in sedentary GW+ wildtype mice compared to active wildtype mice. Future research would benefit from exploring the effects of artificial and training-induced PPAR-delta activation over various time periods. As just 5 mice were used for the training experiments and 8 for the GW experiments, these results should be confirmed using larger and more balanced samples.
Written By: Raishard Haynes, MBS