The field of exercise mimetics is still young, but quite similar at the high level to the more established attempts to find drugs that mimic portions of the calorie restriction response. Exercise and calorie restriction are the two most obvious, well-studied, and reliable means of adjusting the operation of metabolism in order to improve health and extend healthy life span. Sadly, the long-term effects on life span in long-lived species such as our own are nowhere near as large as those exhibited by short-lived species such as laboratory mice. Nonetheless, given that exercise and calorie restriction produce benefits that are larger and more robust than anything that can be achieved for healthy people with presently available medical technology (a state of affairs that we hope will soon change), there is considerable interest in developing drugs that can achieve similar outcomes. In principle at least, these altered states of metabolism have points of control and regulation, a small number of proteins and genes that can be targeted by therapeutics.
Unfortunately the complexity of cellular metabolism, combined with the fact that near all of it changes in response to exercise or calorie restriction, makes it challenging to achieve progress in this field – to find and safely adjust the points of control that must be in there somewhere. Going on for two decades of calorie restriction mimetic research has so far resulted in little to show for the effort involved beyond an incrementally better understanding of some narrow slices of the biochemistry involved. Efforts to produce exercise mimetics may or may not go the same way, but there is certainly no reason to expect it to be any easier. Nonetheless, there are a few promising lines of work underway, such as the one covered by the research materials below. The results presented here are of interest for managing to split out aspects of exercise and endurance into facets that can be adjusted distinctly, rather than for showing positive results in the exercise capacity of mice. The particular drug used in the study was abandoned for human development ten years ago due to concerns about cancer risk. As a tool rather than a potential therapy, it will probably prove to be very useful in further exploration of the biochemistry controlling the short-term and long-term responses to exercise in mammals.
Developing endurance means being able to sustain an aerobic activity for longer periods of time. As people become more fit, their muscles shift from burning carbohydrates (glucose) to burning fat. So researchers assumed that endurance is a function of the body’s increasing ability to burn fat, though details of the process have been murky. Previous work into a gene called PPAR delta (PPARD) offered intriguing clues: mice genetically engineered to have permanently activated PPARD became long-distance runners who were resistant to weight gain and highly responsive to insulin – all qualities associated with physical fitness. The team found that a chemical compound called GW1516 (GW) similarly activated PPARD, replicating the weight control and insulin responsiveness in normal mice that had been seen in the engineered ones. However, GW did not affect endurance (how long the mice could run) unless coupled with daily exercise, which defeated the purpose of using it to replace exercise.
In the current study, researchers gave normal mice a higher dose of GW, for a longer period of time (8 weeks instead of 4). Both the mice that received the compound and mice that did not were typically sedentary, but all were subjected to treadmill tests to see how long they could run until exhausted. Mice in the control group could run about 160 minutes before exhaustion. Mice on the drug, however, could run about 270 minutes – about 70 percent longer. For both groups, exhaustion set in when blood sugar (glucose) dropped to around 70 mg/dl, suggesting that low glucose levels (hypoglycemia) are responsible for fatigue.
To understand what was happening at the molecular level, the team compared gene expression in a major muscle of mice. They found 975 genes whose expression changed in response to the drug, either becoming suppressed or increased. Genes whose expression increased were ones that regulate breaking down and burning fat. Surprisingly, genes that were suppressed were related to breaking down carbohydrates for energy. This means that the PPARD pathway prevents sugar from being an energy source in muscle during exercise, possibly to preserve sugar for the brain. Activating fat-burning takes longer than burning sugar, which is why the body generally uses glucose unless it has a compelling reason not to – like maintaining brain function during periods of high energy expenditure. Although muscles can burn either sugar or fat, the brain prefers sugar, which explains why runners who “hit the wall” experience both physical and mental fatigue when they use up their supply of glucose.
Interestingly, the muscles of mice that took the exercise drug did not exhibit the kinds of physiological changes that typically accompany aerobic fitness: additional mitochondria, more blood vessels and a shift toward the type of muscle fibers that burn fat rather than sugar. This shows that these changes are not exclusively driving aerobic endurance; it can also be accomplished by chemically activating a genetic pathway. In addition to having increased endurance, mice who were given the drug were also resistant to weight gain and more responsive to insulin than the mice who were not on the drug.
In endurance sport competitions such cycling, marathon runs, race walking, and cross-country skiing, “hitting the wall” is a dramatic demonstration of sudden and complete exhaustion. It is thought to be due to the depletion of liver and muscle glycogen and can be averted by training that promotes mitochondrial biogenesis, increased type I fibers, and enhanced fatty acid burning. In this study, we show that PPARδ expression correlates with endurance, and its activation by exercise mimetics, such as GW, is sufficient to increase running time by ∼100 min without changes in either muscle fiber type or mitochondrial biogenesis. Thus, the foundational core of endurance enhancement appears to be purely metabolic. Furthermore, even though the GW impact appears to be achieved via increased fatty acid metabolism, the strongest correlation to endurance is maintenance of blood glucose above 70 mg/dL.
This work identifies PPARδ as both the master regulator and key executor of adaptive changes in energy substrate use in skeletal muscle. Notably, pharmacologic activation of PPARδ replicates the exercise-induced changes in substrate utilization to preserve systemic glucose and thereby delay the onset of hypoglycemia, or “hitting the wall.” While exercise-induced muscle remodeling is well documented, the health benefits have been largely attributed to mitochondrial biogenesis and fiber-type transformation. In contrast, pharmacophores that activate PPARδ promote endurance through preserving glucose, essentially “pushing back the wall,” without affecting mitochondrial biogenesis or fiber-type transformation. This ability to chemically activate energetic circuits regulated by PPARδ has the potential to confer health benefits in a variety of human diseases.