What if I told you there was a way to increase your endurance by 70%? People would be lining up and asking if we have it in pill form, and we almost do. Most people are familiar with the idea of “hitting the wall”. That moment when you are doing some sort of endurFance based activity and you just reach a point where you can’t go on. Maybe your thinking gets cloudy. Your muscles don’t seem to work anymore. Your coordination has suddenly evaporated. That image of the Ironman triathlete, just yards away from the finish line stumbling around. So close to the end but unable to even coordinate those last few steps to get across the finish line.
Generally this is the effect of not having enough glucose in the blood stream to supply the brain with sufficient amounts to meet its energy demands. No matter how badly you want to go, when blood glucose drops too low the brain just says no. Like an automobile engine running out of gas. So the longer you can maintain a higher blood glucose level, the longer you can go before hitting that proverbial wall.
Normally regular endurance exercise has three primary affects that spare blood glucose. 1) The transformation of muscle fibers to types with more oxidative capacity, which equals more energy production out of every gram of glucose used as fuel. 2) An increase in the number and activity of mitochondria, the powerhouses of cells where aerobic metabolism occurs. 3) The improved utilization of fatty acid as a fuel source, sparing the use of blood glucose and our stored carbohydrates in the form of liver and muscle glycogen. Who doesn’t want to use more fat as fuel source.
Of course these changes take a great deal of hard work over a prolonged period of time. As any new runner or average person struggling to lose body fat will tell you, change is difficult, comes slowly and is often hard to notice at all.
Well thanks to a nifty little molecule called peroxisome proliferator-activated receptor delta (PPARδ) we may be able to hack into our normal metabolic processes and accelerate our fat burning capabilities. For the performance athlete this means sparing precious blood glucose and carbohydrate stores which will push the proverbial wall out further, enabling significantly longer, and greater achievements. For the rest of the population the implications are just as significant. Individuals dealing with obesity and other metabolic diseases may have a tool that helps them manage their conditions and make major improvements in their health.
PPARδ is what is known as a nuclear receptor and under normal circumstances it helps kick off the process of the transformation of muscle fibers to more oxidative types along with increasing the use of fatty acids as a fuel source in skeletal muscle. It increases this switch to using fat as fuel through its interaction with two mitochondrial proteins, Cpt1b and Pdk4. Carnitine palmitoyl-transferase 1b (Cpt1b) is an enzyme that limits the rate at which fatty acids are transported into mitochondria. If you enable more fatty acid to enter, you are able to use more of it as fuel. Pyruvate dehydrogenase kinase isozyme 4 (Pdk4) is involved in regulating the use of pyruvate. Pyruvate is a byproduct of the metabolism of carbohydrates and it is then used in another metabolic pathway known as the citric acid cycle (also known as the TCA cycle or Krebs cycle) to produce even more energy. You don’t need to be a molecular biologist to realize that impacting these two gatekeeper molecules can have a major effect on metabolism. And now we know that PPARδ seems to be the key to impacting these two key proteins.
In experiments in which mice are manipulated to have more PPARδ, the mice are able to run twice as long as control subjects (Wang et at., 2004). When the mice are manipulated to not have PPARδ they have problems with the generation of mitochondria and the determination of muscle fiber type (Schuler et al., 2006). If a drug is introduced that activates PPARδ a cascade of positive metabolic and performance benefits are seen.
PPARδ stimulation increases fatty acid metabolism and improves performance
A recent study by Fan et al. (2017) took a closer look at the role of PPARδ and how its manipulation can impact metabolism and performance. This study was conducted in mice but keep in mind we use mice for early experiments because their physiology is very close to humans and the results we see serve as successful stepping stones to studies and interventions in humans. And yes, PPARδ is found and active in humans.
When the authors compared normal mice to ones without PPARδ they found the normal mice showed changes in fuel use from glucose to fatty acid after 4 weeks of running while the mice without PPARδ did not show these same metabolic shifts. Metabolic activity related to the genes impacted by the two gatekeeper proteins, Cpt1b and Pdk4, which are affected by PPARδ were either reduced by 50% or completely absent. Performance wise, the mice missing PPARδ were only able to run half as long as the normal mice. While the shift to fat burning occurred, the mice without PPARδ who ran still saw a change in muscle fiber type and an increase in mitochondria. Clearly it was the fuel source metabolic change that accounted for the increase in performance.
When the authors treated the mice with a drug that activates PPARδ for 8 weeks they found metabolic changes that indicate a significant shift towards increased fatty acid metabolism. There was a strong increase in the expression of the two mitochondrial gatekeeper genes Cpt1b and Pdk4 and a decrease in anaerobic glycolysis (carbohydrate fueled metabolism). When the drug was given to the mine manipulated to not have PPARδ none of the changes that are normally expected occurred indicating that all the metabolic and physiological changes we are concerned with are dependent on muscle PPARδ. Performance wise, the mice given the PPARδ stimulating drug were able to run for 1.5 hours longer then the mice without it.
Increased endurance via blood glucose sparing
The authors theorized that the reason for the increased performance in the drug treated mice was that the increased fatty acid metabolism stimulated via PPARδ spared blood glucose levels. Both drug treated and non-drug treated mice stop running and often pass out once they hit a blood glucose level below 70 mg/dL. In control mice blood glucose levels begin to drop between 90-120 min. In the drug treated mice, blood glucose levels were able to be maintained for extended periods of time and often did not even begin to drop until after 180 minutes. These types of glucose sparing improvements are the same that are seen with exercise training. This switch from glucose to fat fueled metabolism maintains blood glucose levels high enough to continue supporting the needs of the brain and other tissues allowing for the significant increases in performance.
In addition to all of this there was also an up-regulation of 492 genes and a down-regulation of 483 genes within the quadriceps of the tested mice. These included genes that have roles in carbohydrate and fat metabolisms and insulin activity.
So there you have it. PPARδ turns out to be the main regulator of changes in energy substrate use in muscles. Increase its activation and you stimulate muscle cells to use more fat based energy sources, sparing blood glucose and extending performance. The first question you should be asking now is can we take the drug that was used in this study and achieve the same results in humans. The version used in mice is unfortunately not safe for humans however a company has already been set up and is in the process of developing a version that is safe for human consumption. While how to address drugs like this in competitive sport performance is an entirely different problem there is no question it could have significant impacts on a range of metabolically related diseases. So while you are waiting for your PPARδ stimulator in pill form, get out and do some endurance work and stimulate some fat burning/glucose sparing metabolic changes along with enhancing oxidative capacity of muscle fibers and stimulating the growth of additional mitochondria the old fashioned way, by breaking a sweat and doing some work.
Works Cited: Fan, W., Waizenegger, W., Lin, C.S., Sorrentino, V., He, M., Wall, C., Li, H., Liddle, C., Yu, R., Atkins, A., Auwerx, J., Downes, M., and Evans, R. (2017) PPARδ Promotes Running Endurance by Preserving Glucose. Cell Metabolism 25, 1186-1192 Schuler, M., Ali, F., Chambon, C., Duteil, D., Bornet, J.M., Tardivel, A., Desvergne, B., Wahli, W., Chambon, P., and Metzger, D. (2006). PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switch, obesity, and type 2 diabetes. Cell Betab. 4, 407-414. Wang, Y.X., Zhang, C.L., Yu, R.T., Cho, H.K., Nelson, M.C., Bayuga-Ocampo, C.R., Ham, J., Kang, H., and Evans, R.M. (2004) Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol. 2, e294.
