Pushing the envelope.
Leaky calcium channels may contribute to muscle fatigue in super-athletes.

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The Tiredness of the Long-Distance Runner

Even marathon runners and long-distance cyclists have their limits, and a new study may explain why. Based on analyses of athletic mice and humans, a team of researchers suggests that leaky calcium channels can cause muscle fatigue. The group has also identified a new drug that slows that leak in mice, and that may eventually improve human endurance.

The causes of muscle fatigue are elusive. For more than 80 years, physiologists blamed lactic acid, which is produced during exercise and which they believed interfered with muscles' contractile proteins. But in the early 2000s, researchers found that at realistic body temperatures, very little acid accumulates inside muscle cells--and the bit that does may even improve endurance (ScienceNOW, 20 August 2004). Instead, suspicions have turned to the way muscle cells control the movement of calcium.

During normal muscle function, a nerve cell triggers the release of calcium within a muscle cell; the calcium, in turn, prompts the muscle cell to contract. A protein called calstabin binds to calcium channels and ensures that they stay shut until told to open. Physiologist Andrew Marks of Columbia University and colleagues previously reported that, in mice with heart failure, calstabin doesn't bind to the channels as it should. This causes the channels to leak and depletes the supply of calcium needed to trigger contraction, resulting in heart exhaustion. Marks wondered whether the same mechanism might also be behind muscle fatigue.

To find out, Marks's team put a group of mice on an intense marathon-scale training regimen. They made them swim for two 90-minute sessions every day for 2 weeks. Control mice went for only two 15-minute swims per day. The researchers collected several muscle samples from the mice and found that, just as in failing heart muscle, the calcium channels of the more athletic mice had undergone changes that made them chronically leaky and required days of rest to recover.

Humans showed similar changes. When the team analyzed the calcium-channel structure in muscle samples from 12 elite athletes before and after a series of intense cycling sessions, their calcium channels had begun to undergo changes that were "totally parallel" to what had happened in the mice, Marks says.

A new drug could help. Marks's team has developed a compound that it believes could alleviate heart exhaustion, and the researchers created a related drug to test on mice. The drug works by making calstabin bind more tightly to calcium channels. When the team gave the drug to the rodents, the high-exercise mice could run 10% to 20% longer on a treadmill than controls could, the researchers report, even after 3 weeks of extreme exercise.

Muscle physiologist Christopher Ward of the University of Maryland in Baltimore says the work is significant in the context of extreme exercise and may eventually help elite athletes improve their performance. It may even help ease pathological muscle fatigue in ailments such as emphysema, which involves exhaustion of the diaphragm, he says. Still, Ward notes that muscle fatigue is complex and that this one mechanism is only a part of the process. The average person exercising on weekends will get tired well before the calcium leak brings him down, he says.

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