BioEd Online

Researchers have shown how intense exercise can damage muscles, and developed a drug that can hinder the effect in mice. Mice on a taxing work-out schedule were stronger and had more endurance when given the drug.

The drug, called S107, prevents calcium from leaking into muscle cells. Calcium causes muscles to contract, but calcium leaks can reduce the force of contraction and activate an enzyme that chews up muscle protein.

Leaky calcium channels have been associated with the fatigue and soreness that follows intense, sustained exertion, such as running a marathon or long-distance cycling. This weakness can last for days or weeks, and is not the same as the brief discomfort that follows a typical work-out.

Previous work had shown that this long-term muscle fatigue is similar to the weakness felt by patients with heart disease. “If you talk to patients in the hospital with heart failure and you ask them what’s bothering them, the major complaint is that they feel very weak,” says Andrew Marks of Columbia University in New York, and an author on the study.

Marks and his team set out to find a drug that could help to alleviate this fatigue. Marks is involved with a start-up company, called ARMGO Pharma, that plans to develop S107 and others like it for clinical use in patients with chronic tiredness from disease.

But the drug could have other uses. Don Catlin, director of the Olympic Laboratory drug-testing centre at the University of California, Los Angeles, says that a drug such as S107 could also become prime fodder for athletes looking to improve their stamina. “If I were somebody desiring to find a new way to dope and cheat, I would be all over this,” he says.

S107 has not yet been tested in humans. A different class of drugs that blocks calcium channels is already used to treat conditions ranging from high blood pressure to irregular heart beats, but these work differently from S107 and do not improve athletic performance.

Hard-core training

Marks and his colleagues looked closely at mice on an extreme exercise regime, swimming 3 hours a day for 2 weeks. They found that a protein called ryanodine receptor 1, found mainly in skeletal muscle and known to be the biggest player in regulating the cellular flow of calcium, becomes chemically modified in these strained mice. Other proteins that help this receptor to keep calcium channels closed were also depleted in the animals engaged in hard-core training. Mice engineered to lack some of these other proteins fared much worse in endurance tests than normal mice did.

Excess calcium in muscle cells may activate an enzyme called calpain that digests protein, possibly contributing to muscle damage during prolonged exercise.

The group then screened several drugs for a likely candidate to fix the problem, and hit on S107, which stabilizes the ryanodine receptor. Mice following a strenuous workout regime on this drug were able to run for longer and had a stronger grip than did those without the treatment, the team reports in Proceedings of the National Academy of Sciences¹.

A similar mechanism seems to be at work in people, the researchers report. The ryanodine receptor was also modified in the thigh muscles of trained athletes who had been biking hard for three hours on three consecutive days.

Arms race

If S107 can reduce fatigue and increase endurance in people, it will probably be a hit with athletes. Although S107 is in the very early stages of development, Catlin says that he stays abreast of new drug candidates to get a jump start on developing a detection method. “The time lag between a new drug and detection can be several years,” he says — long enough for a few gold medals to be won.

In this case, Catlin is confident that he will be able to develop a test for the drug, a small molecule that he thinks will probably be detectable in urine. The concern, he says, is that the dopers start developing it before pharmaceutical companies undergo the safety and efficacy testing required for approval by the US Food and Drug Administration (FDA). Any side-effects of the drug are unknown, although Marks notes that he has not observed any in mice.

“It’s a fairly simple drug,” Catlin says. “Is the next evil-minded armchair backyard chemist making it as we speak? That’s the way these folks work. They don’t have to worry about the FDA.”