This news story involves a study that, based on the information available about the metabolism during exercise of successful endurance athletes, used pharmaceutical intervention to stimulate a metabolic pathway in mice to give them the benefits of long term training without having done any actual exercise. The eventual goal of this research team is to develop a drug that will provide physical health benefits of exercise to individuals who lack mobility in some way. The benefits involved are increased over a period of time by endurance training, specifically long distance running. There are a couple ways that runners are successful and become more fit over time. The muscles can be trained in this way to preferentially utilize fat as fuel instead of glucose, reducing the body’s reliance on short term energy storage in the form of glycogen. This increases stamina, allowing the body to exercise for longer before fatigue. Another element of being physically fit is sensitivity to insulin, allowing a small amount of insulin to induce cells to take up glucose and a small amount of glucose to find its way more quickly into a cell.
This research team from the Salk Institute has performed multiple studies in this vein, developing a compound called GW1516 to essentially stimulate the peroxisome proliferator activated receptor delta gene in skeletal muscles into epigenetic changes that provide these benefits in mice. They have discovered that giving the compound to sedentary mice over the course of 8 weeks instead of the initial trial of 4 weeks provides the mice a 70% increase in stamina during forced exercise in addition to the change in fatty acid metabolism and insulin sensitivity observed during an earlier study with the same compound. The changes are similar to what are seen in mice that are actually forced to exercise every day unless their PPARd gene is knocked out, in which case they generally are unable to gain the improvements. Inducing expression of this gene has many changes, mostly increasing the rate of fatty acid metabolism and inhibiting glucose metabolism. Cpt1b is an enzyme that helps get fatty acids into the mitochondria of cells and is up-regulated in this scenario. Pdk4 is also up-regulated and inhibits the movement of pyruvate derived from glucose from entering the mitochondria. It was observed in exercise induced PPARd affects that muscle type was altered more in favor of slow twitch and an increase in mitochondria to provide energy faster during exercise. These normal, exercise induced changes were not present in sedentary mice treated with the experimental compound though the health benefits were evident. It is hypothesized that the reduction of glucose uptake by the cells leaves more stored glycogen available to the brain and increasing the time it takes to fatigue. It was observed that the mice were able to run until hypoglycemic but the muscles continued to have fatty acids available to function.
Often with lofty goals such as a product that gives the benefits of exercise without performing any exercise, things don’t turn out as well as hoped. In this case there could be unintended effects from stimulating the PPARd gene that could make this line of inquiry ineffective. Since this gene is minimally understood, a great deal more research needs to be done before there can be confidence that a compound like GW1516 will perform as expected. Since these studies were performed PPARd has been investigated as a target for controlling blood pressure among other things. Skeletal muscle isn’t even near the top of the list for tissues in the body that express this gene with several organs having more PPARd expression. This indicates that the possibility of unintended effects is fairly high. It has been the subject of other studies about athletic performance as well, which are mostly related to the timing and effect of the altered lipid metabolism.
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