Drug improves endurance without need for exercise

For the first time, scientists have developed drugs that mimics the effects of endurance exercise. With the aid of two chemicals, Vihang Narkar, Ronald Evans and colleagues from the Salk Institute managed to turn regular lab rodents into furry Paula Radcliffes - mighty mice that were capable of running further and for longer than their peers. One of the drugs only worked in combination with exercise, but the other managed to boost stamina without it.

Using drugs to boost performance isn't a new development. Steroids can help body-builders to build their bodies, while giving athletes an extra burst of speed. But this is the first time that scientists have managed to develop chemicals that improve stamina, as opposed to strength or speed. One of these drugs only worked when taken in conjunction with exercise, but the other boosted endurance in inactive, couch-potato mice too.

The changes lay in their muscles. The body's skeletal muscles (the ones attached to bones) are made of two major types of fibre - the "fast-twitch" kind that burn sugar, and "slow-twitch" ones that prefer to burn fat. The bulkier fast-twitch varieties contract more quickly and powerfully, and provide short bursts of speed and strength; they are plentiful in the bodies of sprinters and body-builders. The slow-twitch versions are more resistant to fatigue and can carry on working for hours rather than minutes; they are the province of marathon runners and mountain climbers.

Endurance training triggers a suite of genetic changes that converts the fast-twitch fibres into the slow-twitch ones, imbuing the muscle with greater staying power. Narkar's two chemicals emulate the effects of exercise by tapping into the same genetic pathways for reprogramming muscle.

Tale of two chemicals

The first drug carries the uncharismatic name of GW1516 and activates a gene called PPARd. From the start, the gene was a promising target. It controls the metabolism of skeletal muscles, and other groups have managed to double the endurance of laboratory mice by permanently switching it on. So it must have come as a bit of a shock to Narkar's team that feeding mice with GW1516 didn't improve their endurance at all.

Things changed when exercise was thrown into the mix. With a combination of GW1516 and four weeks of daily exercise, mice managed to run for about 70% further and longer than mice that exercised without the drug. By itself, the training improved their stamina by an hour or so, but with the performance-enhancer, they carried on for almost an extra two.  The combination of drug and exercise also substantially increased the proportion of slow-twitch fibres in their muscles and upped the activity of genes involved in burning fats.

The combination of exercise and GW1516 didn't just add their individual benefits together. The combo switched on a unique "signature" of endurance genes, many of which weren't affected by either GW1516 or exercise alone. This signature including several genes involved in fat metabolism and muscle remodelling - a case of the whole being more than the sum of the parts.

The second drug, called AICAR, is even more exciting, for it managed to increase the endurance of mice without a need for exercise. When mice were given the drug, even the inactive ones managed to run 44% farther and 23% longer than their peers. AICAR works by activating a gene called AMPK, which is also involved in muscle metabolism and switched on by exercise. In addition to AMPK, Narkar saw that AICAR switched on a set of 32 genes in the muscles of mice, the majority of which are also controlled by PPARd.

Molecular alliance

In fact, PPARd and AMPK form a close molecular alliance, in which AMPK dramatically boosts the effects that PPARd has on its own target genes. This explains why GW1615 only successes in improving the endurance of mice in conjunction with exercise. GW1615 switches on PPARd but to little effect without the extra boost given by AMPK. Add exercise into the mix, and AMPK is switched on and the alliance can work in tandem.

This collaboration also explains why AICAR improved endurance without the need for extra exercise. Narkar's idea is that AMPK is so central to the genetic events triggered by exercise, that activating it directly with AICAR bypasses the need for any exercise.

That's not to say that exercise is irrelevant - AICAR may have boosted endurance on its own, but not to quite the same extent that exercise normally does. Nonetheless, by chemically mimicking some of the benefits of exercise, the team's hope is that the drugs will find a use in treating metabolic diseases such as obesity, or warding against muscle wasting and frailty. After all, keeping active has a wide range of benefits that go well beyond its effects on endurance.

There's even some evidence to suggest that Narkar's drugs may do more good than simply improving stamina. In some of the mice, they triggered fat loss as alongside increased endurance. PPARd controls hormone levels and heart muscle as well as skeletal muscle, while AMPK's ability to lower blood sugar levels may be relevant to diabetics. The potential benefits (and risks) of manipulating these genes won't be fully known until Narkar checks their effects in these other tissues.

For now, the main risk has to the potential for cheating in athletics tournaments. Narkar's team haven't confirmed if the drugs would have the same effects in humans, but there is evidence that GW1615 at least is active in the human body. It's not clear if this sort of pharmaceutical stimulation could ever top the type of benefits that hard athletic training can bring, or even if they would have any effects in people who have already pushed their bodies to the limits of endurance. Even so, the researchers have already spoken to the World Anti-Doping Agency about developing a test that detects the use of PPARd-boosting drugs.

Reference: Cell 10.1016/j.cell.2008.06.051