By GINA KOLATA
One of the great unanswered questions in physiology is why 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.

What did make muscles tired?

The new work in mice, Dr. Brooks 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 David 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. 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.”

Posted by energydoc at 09:04 PM | Permalink

By ALAN FINDER
LOS ALTOS, Calif. — “Can we take a look at your backpack?”

Ana Homayoun repeats that question countless times a day. No, she does not screen airline passengers or work security at a basketball arena.

Ms. Homayoun is a tutor. She helps teenagers with subjects like math and science, but she particularly specializes in teaching boys how to become more organized.

One afternoon in her cozy office suite in this affluent suburb south of San Francisco, she asked John Ferrari, 14, to go through a two-inch stack of papers he pulled from his backpack. He sorted through the papers, placing them in separate piles — writing, spelling, vocabulary, tests — to bring order to his loose-leaf binder.

“Oh, here’s my class schedule, what a relief,” said John, an eighth grader.

A moment later, he stumbled across something even more valuable. “I have to turn this in tomorrow,” John said. “It’s the name I want on my diploma.”

With girls outperforming boys these days in high school and college, educators have been sparring over whether there is a crisis in the education of boys. Some suggest the need for more single-sex schools, more male role models or new teaching techniques. Others are experimenting with physical changes in classrooms that encourage boys to move around, rather than trying to anchor them to their seats.

But as they debate, high-priced tutors and college counselors have jumped into the fray by charging as much as $100 an hour and up to bring boys to heel.

The tutors say their main focus is organizational skills because boys seem generally to have more difficulty getting organized and multitasking than girls do.

And so private counselors in places as diverse as Chicago, New York City, Sarasota, Fla., and Bennington, Vt., who guide juniors and seniors in applying to college, have devised elaborate systems — from color-coded, four-month calendars that mark dozens of deadlines to file boxes that students must take to each session.

Donna Goldberg began working with students in Manhattan on how to get organized 17 years ago. Her inspiration was her own son, then in seventh grade. Mrs. Goldberg was astonished to learn that he had not been turning in any homework.

“He opened his backpack, which was really a black hole, and he said, ‘Here it is,’ ” she said. He had not understood that in seventh grade he was responsible for handing in his homework, instead of waiting to be asked.

Some educators think the tutors are on the right track, whether or not there is science to back them up. “The guys just don’t seem to develop the skills that involve organization as early,” said Judith Kleinfeld, a psychology professor at the University of Alaska and founder of the Boys Project, a coalition of researchers, educators and parents to address boys’ problems.

Mrs. Goldberg, Ms. Homayoun and other private tutors say boys must learn not only how to organize, but also how to manage their time and even how to study.

Robert Gittings, a sixth grader, has been coming weekly to work with Ms. Homayoun since September. He, too, is asked to empty his backpack, and on one visit, cheerfully removed a vast collection of textbooks, binders, workbooks, paperback books and hardcover library books.

Most of the binders were orderly and reasonably neat. But there was a stack of papers from science, nearly an inch thick, that needed to be sorted.

“Do you have homework for tonight?” Ms. Homayoun asked.

He replied, “We have a work sheet.” But it was not in the homework section of the science binder or in his daily planner.

Then Robert remembered where he put it. From a side pocket of his backpack, he pulled a sheet of paper that has been folded into a tiny rectangle.

Ms. Homayoun laughed and said gently, “Maybe we should put that in the homework section?”

Ms. Homayoun opened her business, Green Ivy Educational Consulting, not long after graduating from Duke University in 2001. She created her organizational system — basically an elaboration of the ways she studied in high school — after she began tutoring six years ago.

“I would ask, What’s the class that troubles you the most?” she said. “I would ask to see the binder, and it would always be the messiest.”

She requires her clients to have a three-ring, loose-leaf binder for each academic subject, to divide each binder into five sections — notes, homework, handouts, tests and quizzes, and blank paper — and to use a hole puncher relentlessly, so that every sheet of school-related paper is put into its proper home.

Students must maintain a daily planner; they are required to number the order in which they want to do each day’s homework and draw a box next to each assignment, so it can be checked off when completed.

Homework must be done in a two-hour block in a quiet room, with absolutely no distractions: no instant messaging, no Internet, no music, no cellphone, no television.

While some girls need help getting organized, at least three-quarters of her students are boys, Ms. Homayoun said. Girls usually adopt her methods more quickly.

“Girls pick up on this much faster,” said Ms. Homayoun, 28, who has a relaxed but firm manner and a gift for diplomacy with teenagers and their parents. “Boys, you still have to be on them for a while. They’re not going to pick up on it immediately. You have to roll with it.”

Two seniors arrived for weekly appointments, expecting to complete their college applications and file them online. But the tutor discovered that one boy left out sections of basic personal information on his application, while the other missed a requirement for three short essays by the University of Virginia. Each was disappointed that there was more work to do.

“Sorry,” she consoled one. “It’s like thinking you’ve finished a marathon and finding out you have three miles left.”

With guidance and constant follow-up, boys can make significant progress, Ms. Homayoun said. Ernie McMillan, 17, a high school senior who has been working with her since the summer before his junior year, is one example. He created orderly binders, kept on top of his daily planner, took notes while reading and even agreed to eliminate distractions during homework.

In the spring of his sophomore year, Mr. McMillan had a 2.8 grade-point average, a B-minus. After working with Ms. Homayoun, he raised his average to 3.1 in the first semester of his junior year. Last spring, he brought it up to 3.5, a B-plus.

“I was really happy about that,” he said. “I always thought I could do it, and I didn’t understand why I couldn’t. I just needed that backing, that structure. I was turning in my assignments on time. I was working ahead on my classes. I was organized in a way I never had been before.”

Mr. McMillan stopped for a moment, before adding, “She totally reworked my backpack, too.”

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Posted by energydoc at 11:27 AM | Permalink