Finding May Solve Riddle of Fatigue in Muscles

[Guest guest]

Finding May Solve Riddle of Fatigue in Muscles

http://www.nytimes.com/2008/02/12/health/research/12musc.html?

_r=1 & ex=1360558800 & en=2f1fd79a3e514fb1 & ei=5088 & partner=rssnyt & emc=rss &

oref=slogin

By Kolata

A New Explanation of Muscle Fatigue

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. 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 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.

What did make muscles tired?

The new work in mice, Dr. said, " is exciting and provocative. "

It is a finding that came unexpectedly from a very different line of

research. Dr. Marks, a cardiologist, wanted to discover better ways

to treat people with congestive heart failure, a chronic and

debilitating condition that affects an estimated 4.8 million

Americans.

Its hallmark is a damaged heart, usually from a heart attack or high

blood pressure. Struggling to pump blood, the heart grows, sometimes

becoming so large that it fills a patient's chest. As the disease

progresses, the lungs fill with fluid. Eventually, with congested

lungs and a heart that can barely pump, patients become so short of

breath that they cannot walk across a room. Half die within five

years.

In his efforts to understand why the heart muscle weakened, Dr. Marks

focused on the molecular events in the heart. He knew the sequence of

events. As the damaged heart tries to deal with the body's demands

for blood, the nervous system floods the heart with the fight or

flight hormones, epinephrine and norepinephrine, that make the heart

muscle cells contract harder.

The intensified contractions, Dr. Marks and his colleagues

discovered, occurred because the hormones caused calcium to be

released into the heart muscle cells' channels.

But eventually the epinephrine and norepinephrine cannot stimulate

the heart enough to meet the demands for blood. The brain responds by

releasing more and more of those fight or flight hormones until it is

releasing them all the time. At that point, the calcium channels in

heart muscle are overstimulated and start to leak.

When they understood the mechanisms, 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.

Dr. Marks and his colleagues altered the drugs to make them less

toxic and to rid them of their ability to block calcium channels.

They were left with drugs that stopped calcium leaks. The

investigators called the drugs rycals, because they attach to the

ryanodine receptor/calcium release channel in heart muscle cells. The

investigators tested rycals in mice and found that they could prevent

heart failure and arrhythmias in the animals. Columbia obtained a

patent for the drugs and licensed them to a start-up company, Armgo

Pharma of New York. Dr. Marks is a consultant to the company.

It hopes to start testing one of the drugs for safety in patients in

the spring, but the tests will not be at Columbia because of the

university and investigators' conflicts of interest. In the meantime,

Dr. Marks wondered whether the mechanism he discovered might apply to

skeletal muscle as well as heart muscle. Skeletal muscle is similar

to heart muscle, he noted, and has the same calcium channel system.

And heart failure patients complain that their muscles are extremely

weak.

" If you go to the hospital and ask heart failure patients what is

bothering them, they don't say their heart is weak, " Dr. Marks

said. " They say they are weak. "

So he and his colleagues looked at making mice exercise to

exhaustion, swimming and then running on a treadmill. The calcium

channels in their skeletal muscles became leaky, the investigators

found. And when they gave the mice their experimental drug, the

animals could run 10 to 20 percent longer.

Then, collaborating with Nieman, an exercise scientist at

Appalachian State University in Boone, N.C., the investigators asked

whether the human skeletal muscles grew tired for the same reason,

calcium leaks.

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.

Dr. Nieman removed snips of thigh muscle from all the athletes after

the third day and sent them to Columbia, where Dr. Marks's group

analyzed them without knowing which samples were from the exercisers

and which were not.The results, Dr. Marks said, were clear. The

calcium channels in the exercisers leaked. A few days later, the

channels had repaired themselves. The athletes were back to normal.

Of course, even though Dr. Marks wants to develop the drug to help

people with congestive heart failure, hoping to alleviate their

fatigue and improve their heart functions, 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. Liggett, a heart-

failure researcher at the University of land. 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. "