Why do muscles get tired? The experience is universal, common to creatures that have muscles, but the answer has been elusive until now.

Scientists at Columbia say they have not only come up with an answer, but have also devised, for mice, an experimental drug that can revive the animals and let them keep running long after they would normally flop down in exhaustion.

For decades, muscle fatigue had been largely ignored or misunderstood. Leading physiology textbooks did not even try to offer a mechanism, said Dr. Andrew Marks, principal investigator of the new study. A popular theory, that muscles become tired because they release lactic acid, was discredited not long ago.

In a report published Monday in an early online edition of Proceedings of the National Academy of Sciences, Dr. Marks says the problem is calcium flow inside muscle cells. Ordinarily, ebbs and flows of calcium in cells control muscle contractions. But when muscles grow tired, the investigators report, tiny channels in them start leaking calcium, and that weakens contractions. At the same time, the leaked calcium stimulates an enzyme that eats into muscle fibers, contributing to the muscle exhaustion.

In recent years, says George Brooks of the University of California, Berkeley, muscle researchers have had more or less continuous discussions about why muscles fatigue. It was his work that largely discredited the lactic-acid hypothesis, but that left a void.

The researchers developed a class of experimental drugs that block the leaks in calcium channels in the heart muscle. The drugs were originally created to block cells' calcium channels, a way of lowering blood pressure.

The reasearchers tested highly trained bicyclists rode stationary bikes at intense levels of exertion for three hours a day three days in a row. For comparison, other cyclists sat in the room but did not exercise.

The calcium channels in the exercisers leaked. A few days later, the channels had repaired themselves. The athletes were back to normal.

Although the drug was created to help people with congestive heart failure,  athletes might also be tempted to use it if it eventually goes to the market.

The odds are against this particular drug being approved, though, cautions Dr. W. Robb McClellan, a heart disease researcher at U.C.L.A.

"In heart failure, there are three medications that improve mortality, but there have probably been 10 times that many tested," he said.

Even if the first drug that prevents calcium leaks does not work in patients, Dr. McClellan added, the important advance is to understand the molecular events underlying fatigue. "Then," he said, "you can design therapies."

So the day may come when there is an antifatigue drug.

That idea, "is sort of amazing," said Dr. Steven Liggett, a heart-failure researcher at the University of Maryland.  Yet, Dr. Liggett said, for athletes "we have to ask whether it would be prudent to be circumventing this mechanism."

"Maybe this is a protective mechanism," he said. "Maybe fatigue is saying that you are getting ready to go into a danger zone. So it is cutting you off. If you could will yourself to run as fast and as long as you could, some people would run until they keeled over and died."

(New York Times, February 12, 2008)