[tt] NYT: Couch Mouse to Mr. Mighty by Pills Alone

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This is fabulous news! 101-year old blind couch potatoes will be able to 
run on a treadmill twice as long before exhaustion. See following article.

Couch Mouse to Mr. Mighty by Pills Alone
New York Times, 8.8.1
http://www.nytimes.com/2008/08/01/science/01muscle.html

By NICHOLAS WADE

For all who have wondered if they could enjoy the benefits of
exercise without the pain of exertion, the answer may one day be yes
-- just take a pill that tricks the muscles into thinking they have
been working out furiously.

Researchers at the Salk Institute in San Diego reported that they
had found two drugs that did wonders for the athletic endurance of
couch potato mice. One drug, known as Aicar, increased the mice's
endurance on a treadmill by 44 percent after just four weeks of
treatment.

A second drug, GW1516, supercharged the mice to a 75 percent
increase in endurance but had to be combined with exercise to have
any effect.

"It's a little bit like a free lunch without the calories," said Dr.
Ronald M. Evans, leader of the Salk group.

The results, Dr. Evans said, seem reasonably likely to apply to
people, who control muscle tone with the same underlying genes as do
mice. If the drugs work and prove to be safe, they could be useful
in a wide range of settings.

They should help people who are too frail to exercise and those with
health problems like diabetes that are improved with exercise, Dr.
Evans said.

The chemicals involved are already available, and such
muscle-enhancing drugs would also have obvious appeal to athletes
seeking to gain an edge in performance. Dr. Evans said athletes
often showed up at public lectures he had given and asked him about
the drugs.

With money from the Howard Hughes Medical Institute, Dr. Evans has
devised a test to detect whether an athlete has taken the drugs and
has made it available to the World Anti-Doping Agency, which
prepares a list of forbidden substances for the International
Olympic Committee. Officials at the anti-doping agency confirmed
that they were collaborating with Dr. Evans on a test but could not
say when they would start using it.

Experts not involved in the study agreed that the drugs held promise
for treating disease. Dr. Johan Auwerx, a specialist in metabolic
diseases at the University Louis Pasteur in Strasbourg, France, said
the result with Aicar looked "pretty good" and could be helpful in
the treatment of diabetes and obesity. "The fact you can mimic
exercise is a big advantage," he said, "because diet and exercise
are the pillars of diabetes treatment."

Dr. Richard N. Bergman, an expert on obesity and diabetes at the
University of Southern California, said the drugs might prove to
have serious side effects but, if safe, could become widely used.
"It is possible that the couch potato segment of the population
might find this to be a good regimen, and of course that is a large
number of people."

The idea of a workout in a pill seems almost too good to be true,
but Dr. Evans has impressive research credentials, including winning
the Lasker Award, which often presages a Nobel Prize. He is an
expert on how hormones work in cells and on a powerful
gene-controlling protein called PPAR-delta, which instructs fat
cells to burn off fat.

Four years ago he found that PPAR-delta played a different role in
muscle. Muscle fibers exist in two main forms. Type 1 fibers have
copious numbers of mitochondria, which generate the cell's energy
and are therefore resistant to fatigue. Type 2 fibers have fewer
mitochondria and tire easily. Athletes have lots of Type 1 fibers.
People with obesity and diabetes have far fewer Type 1 and more Type
2 fibers.

Dr. Evans and his team found that the PPAR-delta protein remodeled
the muscle, producing more of the high-endurance Type 1 fiber. They
genetically engineered a strain of mice whose muscles produced extra
amounts of PPAR-delta. These mice grew more Type 1 fibers and could
run twice as far as on a treadmill as ordinary mice before
collapsing.

Given that people cannot be engineered in this way, Dr. Evans
wondered whether levels of the PPAR-delta protein could be raised by
drugs. Pharmaceutical companies have long tried to manipulate
PPAR-delta because of its role in fat metabolism, and Dr. Evans
found several drugs were available, although they had been tested
for different purposes.

In a report in the Friday issue of Cell, he described the two drugs
that successfully activate the muscle-remodeling system in mice,
generating more high-endurance Type 1 fiber. The drug GW1516
activates the PPAR-delta protein but the mice must also exercise to
show increased endurance. It seems that PPAR-delta switches on one
set of genes, and exercise another, and both are needed for
endurance.

Aicar improves endurance without training. Dr. Evans believes that
it both activates the PPAR-delta protein and mimics the effects of
exercise, thus switching on both sets of genes needed for the
endurance signal.

Aicar signals to the cell that it has burned off energy and needs to
generate more. The drug is "pretty much pharmacological exercise,"
Dr. Evans said.

He said the drugs worked off a person's genetics, pushing the body
to an improved set-point otherwise gained only by strenuous
training. "This is not just a free lunch," he said. "It's pushing
your genome toward a more enhanced genetic tone that impacts
metabolism and muscle function. So instead of inheriting a great
set-point you are using a drug to move your own genetics to a more
activated metabolic state."

Aicar has been tested for various diseases since 1994 and is in
advanced trials for treating a heart condition known as ischemic
reperfusion injury. But neither Aicar nor GW1516 has been tested in
people for muscle endurance, so the side effects of the drugs,
particularly over the long term, are not precisely known.

That may change if pharmaceutical companies pursue Dr. Evans's
findings. "The drugs' effect on muscle opens a window to a world of
medical problems," he said. "This paper will alert the medical
community that muscle can be a therapeutic target."

The drugs activate at least one of the chemical pathways triggered
by resveratrol, a substance that also showed increased endurance in
mice. Resveratrol is found in red wine though in amounts probably
too low to significantly affect muscle.

In 2006 Dr. Auwerx and colleagues at University Louis Pasteur showed
that large doses of resveratrol would make mice run twice as far as
usual on a treadmill before collapsing. It is unclear just how
resveratrol works, but one of its effects may be to bind with a
protein that helps activate PPAR-delta. Dr. Auwerx's
resveratrol-treated mice remodeled their muscle fibers into the Type
1, with greater endurance.

That is the same result Dr. Evans has found can be obtained with
Aicar. The relationship between the two drugs is not yet clear. Dr.
Evans believes that resveratrol acts on so many pathways in the
cell, particularly at high doses, that it is hard to know how it is
achieving any given effect, whereas the role of Aicar and GW1516 is
well defined. But Dr. Auwerx said he did not think Aicar was
necessarily working in the way Dr. Evans described.