New Muscle Drugs Could Be The Next Big Thing In Sports Doping

Research intended to help people with muscle-wasting diseases could be about to launch a new era in performance enhancing drugs.

The research has produced several muscle-building drugs now being tested in people with medical problems, including muscular dystrophy, cancer and kidney disease. The drugs all work by blocking a substance called myostatin that the body normally produces to keep muscles from getting too big.

And it’s likely that at least one of the drugs will receive FDA approval in the next few years, researchers say.

“When the myostatin inhibitors come along, they’ll be abused,” says Carlon Colker, a bodybuilder and a physician in Greenwich, Conn., who works with professional athletes. “There’s no question in my mind.”

One reason is that athletes and bodybuilders have seen pictures of animals like Belgian Blue bulls, which naturally lack myostatin and appear to be made of muscle. “They’re huge,” Colker says. “I mean they’re ridiculous looking.”

If myostatin inhibitors do catch on as performance enhancing drugs, they will become part of a larger trend in sports doping. A decade ago, performance enhancing drugs often came from rogue chemists in unregulated labs. These days, athletes are using FDA-approved products from major pharmaceutical companies.

Lance Armstrong and many other cyclists relied on the anemia drug known as EPO. Baseball players including Alex Rodriguez of the New York Yankees have been linked to another FDA-approved product, human growth hormone.

Some Muscular Mice

Athletes and bodybuilders have been fascinated by myostatin ever since it was discovered in the 1990s by a researcher at Johns Hopkins named Se-Jin Lee. And if you visit Lee’s mouse lab, you can see why the discovery got so much attention.

The secured facility is filled with rows of plastic cages containing some very muscular mice. “They look bulked up,” he says, and they are. Lee gestures toward the cages on one shelf. “Those mice,” he says,”have about twice the muscle mass of normal mice.”

The mice he’s talking about have been genetically engineered to lack the myostatin gene. That means their bodies don’t produce the myostatin protein.

Normally, myostatin has two important roles, Lee says. In a developing embryo, it acts to limit the number of muscle fibers that are formed. Later in life, it acts to limit the growth of those muscle fibers.

“So when you get rid of the myostatin gene entirely, you see more muscle fibers, and then you get bigger muscle fibers,” Lee says.

To illustrate his point, Lee sets the two plastic mouse cages on a stainless steel bench. He opens the lid of one cage and pulls out a mouse by its tail. “This mouse here is a normal male mouse about two months old,” he says.

Then Lee reaches into the second cage. “Here’s one of these myostatin knockout mice,” he says. “I think you can appreciate how much extra muscle these mice have.” It’s hard to miss. The animal is not only much larger, but beneath its fur is a bodybuilder’s physique.

Lee says he knew from the start that his discovery was going to get a lot of attention. “You only have to look at those mice for 10 seconds to realize not only the potential to treat patients, but also the potential for abuse,” he says.

Athletes weren’t the only ones who saw the potential for abuse. In 2008, the World Anti-Doping Agency banned substances that inhibit myostatin.

Treating Muscles That Have ‘Melted Away’

If myostatin drugs do reach the market, they could help tens of thousands of patients with genetic diseases like muscular dystrophy. The drugs also might help a much larger number of people with muscle wasting associated with cancer, or kidney disease or even old age.

And myostatin inhibitors could do a lot for otherwise healthy people who simply suffer an injury like a blown-out knee, says Chris Mendias, a researcher who works with orthopedic patients at the University of Michigan.

“We have to put you in a brace. You have to be non-weight-bearing for a time,” he says. “The muscle will atrophy. And in a lot of cases as hard as we try, the muscle mass never comes back.”

Myostatin appears to contribute to this atrophy, Mendias says. Studies show that levels of the protein rise dramatically when people stop using a particular muscle. And you can see the result in patients who have torn the knee’s anterior cruciate ligament.

“It literally looks like the muscle has kind of melted away,” he says. “So [we think] that if you used a myostatin inhibitor for a short period, that might actually be beneficial in preventing the atrophy later on.”

Another researcher with high hopes for myostatin is physiologist Lee Sweeney, who studies muscle diseases at the University of Pennsylvania. But Sweeney’s optimism about new treatments is tempered by his concern about doping.

Nearly a decade ago, Sweeney wrote an article in Scientific American warning that myostatin manipulation could become a big problem in sports. At the time, he thought athletes might undergo gene therapy to permanently block myostatin.

Now, he says, it looks like myostatin-blocking drugs will provide a cheaper, easier and more attractive option. For one thing, Sweeney says, these products will probably leave no trace once an athlete stops taking them.

“They would have a finite sort of time that they would reside in the body and then they would be cleared,” he says. “And so, unlike gene therapy, if you timed it right you might not be able to detect that they had been used.”

Sweeney fears that myostatin drugs will become notorious doping agents. Then, he says, doctors may hesitate to prescribe them for legitimate uses, like helping patients with cancer or kidney disease who can no longer walk because they have lost so much muscle.

“The sort of unmet need in all these diseases far outweighs whether somebody wins a bicycle race or a sprinting event because they cheated,” he says.

The Story Of EPO

If the FDA does approve a myostatin inhibitor, it will probably be for a very specific group of patients. But once a drug is on the market, doctors can prescribe it to just about anyone. That’s how the anemia drug EPO became such a big success after it was approved in 1989, says Jerry Avorn from Harvard Medical School.

EPO itself wasn’t the problem, Avorn says.

“EPO is a wonderful drug,” he says. “It does fantastic things to increase the red blood cell count and to treat anemia. And when used appropriately it’s one of the best drugs that’s been discovered in the last 50 years.”

But no one expected this costly and potentially dangerous drug to be used by millions and millions of people, Avorn says.

“When EPO was first approved, it was approved as an orphan drug — a drug that was supposed to be used by under 200,000 people total in the U.S.,” he says. “It turned out to be used by enormously greater numbers of people, partly for good reasons, partly for bad reasons.”

Initially, EPO was indicated only for patients who had anemia caused by kidney failure. The FDA later added patients with anemia related to cancer chemotherapy. Then a combination of aggressive marketing and off-label prescribing helped EPO reach a whole lot of people who didn’t have cancer or kidney disease, Avorn says.

“I’ve had colleagues who have had patients come to them and say, ‘Doc, I saw an ad for this EPO stuff on TV last night and I’d like you to give me some because I’d like to have a little more oomph.’ “

Eventually, EPO became the most successful biotech drug in history. Global sales reached $10 billion a year despite growing evidence that high doses could cause heart problems and even death.

With so much EPO around, it’s hardly surprising that some of it went to healthy athletes, Avorn says. “People — including Lance Armstrong — figured out that if you’re in a bicycle race and you’ve got more red cells than the other people, then you will have more oxygen carrying capacity and more energy and be able to bike faster,” he says

The Future Of Myostatin Drugs

So now the question is, will drugs that inhibit myostatin become the next EPO?

“It’s possible,” says Colker, the physician and bodybuilder. Athletes and bodybuilders are constantly looking to medical research for the next product that will give them an edge, he says. And once a new product is widely used, people start looking for the next new thing.

The doping arms race is a bit like a cartoon, Colker says. “Daffy Duck comes out with a slingshot. And then Bugs Bunny comes back with a bat. And then Daffy Duck goes off and comes back with a gun, and then Bugs Bunny goes off and comes back with a bazooka, and then Daffy Duck goes off and comes back with an Army tank,” he says. “It just keeps going and going and going.”

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