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Gene Tweaking Turns Couch Potato Mice Into Racers
By Maggie Fox, Health and Science Correspondent
Mon 23 August
Reuters
Altering a single gene turned ordinary mice
into marathon racers that could run for hours and eat huge amounts
of food without getting fat, a team of researchers reported on
Monday.
They said their study could lead to an exercise pill that gives many
of the benefits of training without the need to sweat.
"It is a pill that, in part, mimics exercise. It mimics the
metabolic activity associated with exercise," Howard Hughes Medical
Institute investigator Ronald Evans of The Salk Institute for
Biological Studies, who led the study, said in a telephone interview.
Evans and a team of researchers were looking at a gene called
PPAR-delta -- a master regulator of different genes.
Revving up PPAR-delta had been shown to help raise metabolism and
fat-burning, Evans said. "Part of our goal is the development of
treatments for metabolic disease, diabetes and obesity," he said.
Writing in the journal Public Library of Science Biology, Evans and
colleagues said they tweaked the PPAR-delta gene to stay in a
permanently "on" position and then genetically engineered mice with
it.
They expected to see changes in metabolism but were surprised at how
extensive they were.
The genetically engineered mice could run for an hour longer than
normal mice, "which translates to nearly a kilometer (half a mile)
further," the researchers wrote.
And when fed a high-fat diet, the normal mice became fat while the
genetically altered mice gained no weight. Tests showed they were
burning off the fat even when they did not exercise, Evans said.
"They are both good runners and they don't gain weight easily,"
Evans said.
The mice grew more slow-twitch muscle fibers -- the kind used by the
body for endurance-type exercise, as opposed to the fast-twitch
muscles used for sprinting.
Evans said he is still studying the, which are now about 9 months
old.
"One of the questions for the future is studying the impact this has
on longevity," he said. "So far, there are no side effects other
than that they are resistant to weight gain. They are fertile and
they are able to give rise to the next generation of long-distance
runners."
Other studies have led researchers to believe an "exercise pill" is
possible. In 2002, researchers published a study in the journal
Science showing that increasing production of an enzyme called
calmodulin-dependent protein kinase or CaMK could have similar
effects.
"There are several studies that have reported fiber-type switches,"
Evans said. "What is different about this one is we looked at what
the consequences of that fiber-type switch are."
While Evans and colleagues used genetic manipulation, they said
using a pill to create a similar effect is already possible.
They gave normal mice an experimental drug called GW501516 that also
activates PPAR-delta. The drug is being developed by GlaxoSmithKline
to treat people with fat metabolism disorders.
Normal mice given the drug could eat a high-fat diet without gaining
weight, Evans said.
Evans said he is a consultant to Ligand Pharmaceuticals, which
developed the drug and licensed it to Glaxo.
Evans said the findings confirm that PPAR-delta is important to the
development of slow-twitch muscles and confirm that, barring the
development of an exercise pill, that there is no easy way to chow
down and keep the weight off.
"That's the catch. You can only do it now by exercising," Evans said.
"And what you want to do is use the slow-twitch motor neuron -- move
slowly. People who exercise tend to want to do it fast, and they
want to lift the weights fast."
'Marathon Mice' created to run farther, longer
PAUL ELIAS
AP
Tuesday, August 24, 2004
"Genetic doping" of elite athletes moved a step closer to
reality after researchers unveiled genetically engineered mice
that can run farther and longer than their naturally bred
brethren.
The creation of the so-called marathon mice, announced Monday,
follows earlier genetic engineering work that created
"Schwarzenegger mice," rodents that bulked up after getting
injected with muscle-building genes.
The engineered mice racing away on their treadmills are bound
to add to the furor over performance-enhancing substances,
just as the world's best marathoners prepare for the Olympic
event Sunday.
The gene engineered in these mice essentially mimics exercise:
Researchers say it conferred endurance and prevented the
modified mice from becoming obese -- even when they were kept
inactive and fed a high-fat diet.
"This is a real breakthrough in our understanding of exercise
and diet and their effects on obesity," said lead researcher
Ronald Evans of the Salk Institute in San Diego. "The
practical use of this discovery is the implication in
controlling weight."
The paper describes how engineered mice, even the couch potato
variety, were able to run farther and longer if their "fat
switch" genes remain switched on continuously. The engineering
also appeared to make them immune to obesity.
Evans found the gene he dubbed the "fat switch" more than 10
years ago, but it is only just now that its broad implications
are being understood. Evans now believes his work has
implications for just about every disease of the metabolism,
from obesity to heart disease.
"This gives us a real lever on metabolism," Evans said.
Of course, nobody cares more about the intricacies of the
human metabolism than Olympic athletes -- and for better or
worse, Evans is bracing for a flood of inquiries from their
trainers now that his research paper has been published in the
online journal Public Library of Science Biology.
Many predict that steroids, growth hormones and other drugs
and chemicals that cheating athletes take to shave the
smallest sliver of a second off their times will soon seem
quaint -- replaced by hard-to-detect genetic engineering,
which could become commonplace as soon as the Beijing Olympics
four years from now.
Instead of improving times by fractions of a second, the
genetically enhanced marathon mice ran twice as far and nearly
twice as long as naturally bred rodents.
The engineered mice ran 1,800 meters before quitting and
stayed on the treadmill an hour longer than the natural mice,
which were able to stay running for 90 minutes and travel 900
meters. Evans said he has not seen any adverse side effects in
the engineered mice.
Evans expects his research will be of keen interest to the
Olympic officials who struggle to keep athletes honest. "It's
a bit ironic that we developed these marathon mice at the same
time of the Olympics," he said.
Evans and his team made the marathon mice to help them better
understand diseases of the metabolism such as obesity and
diabetes. The bulked-up "Schwarzenegger mice" serve a
different purpose -- research into muscular dystrophy
treatments.
The "fat switch" gene, when switched on, begins the process of
creating "fatigue-resistant" muscles while helping the heart
and nervous system create endurance.
Humans run and jump thanks in large part to two types of
muscle, known as "fast twitch" and "slow twitch." Depending on
workout regimens, fast twitch is converted into slow twitch or
vice versa.
Sprinters crave fast twitch, which confers speed at the cost
of endurance. Marathoners work to bulk up slow twitch for the
opposite reason. Elite athletes are continuously probing their
muscles to ensure they have the right ratio of fast- and
slow-twitch muscles.
Evans' team found that slow twitch converted into fast twitch
only when the gene in charge of the process kicked on, which
was only when the mice exercised. That is a problem for couch
potatoes with Olympic-sized goals.
So Evans took a piece of genetic material known as a promoter,
or "gene switch," and injected it into the mice, keeping the
gene on continuously. As a result, even the laziest mice
increased endurance.
"The enhanced performance of the mouse could translate into
human athleticism," Evans said.
There's a big gulf between mice and men, and the field of gene
therapy has yielded mixed results over the last decade,
including the death of a human subject five years ago.
Still, Evans' earlier work is already being tested in people.
The pharmaceutical company GlaxoSmithKline PLC is conducting
mid-stage human experiments with a chemical that turns on the
"fat switch" in hopes of developing a drug to raise levels of
"good cholesterol."
"This may represent a significant role in exercise endurance,"
said Glaxo spokesman Rick Koening.
After Evans' latest work was published on Monday, Koenig added
a cautionary note: "We do not condone the pharmaceutical
enhancement of athletes."
[Link]
Geneticists engineer marathon mice
Endurance animals point way to athletic enhancement
news@nature.com
23 August 2004
Helen Pearson
They can run like Haile Gebrselassie, but these champions are
cheats. US scientists have genetically engineered two types of mice
with exceptional athletic stamina, raising concerns that athletes
might try to use similar strategies.
Marathon runners have far higher physical endurance than an average
person does. One reason is that their muscles have a greater
capacity to generate energy aerobically, using oxygen. This
mechanism allows them to keep producing energy for long periods of
time, as opposed to anaerobic activity, which powers short,
explosive bursts, such as sprints.
Now two teams of scientists have hit upon molecules that might
explain some of this muscular staying power. Ronald Evans of the
Salk Institute for Biological Studies in San Diego, California,
engineered mice to burn fat not sugar, and Randall Johnson of the
University of California, San Diego, created mice that were less
able to switch to anaerobic activity.
Aerobic boost
Evans and his team tweaked the genes of mice so that they
permanently switched on production of a protein called PPARdelta,
which switches muscles from burning sugar to burning fat. Because
fat must be metabolized aerobically, this limits a muscle's
anaerobic activity.
Like seasoned marathoners, the engineered mice outpaced the
competition on a rodent-sized treadmill, Evans found, scampering
nearly twice as far before becoming as exhausted as a comparison
group. The animals, which the team dubbed 'marathon mice', had far
more of the muscle fibres that work aerobically, and fewer of those
that burn anaerobically, the team reports in PLoS Biology.
The finding is "very exciting" as it fits with what is known about
endurance athletes, says exercise physiologist Frank Booth at the
University of Missouri, Columbia. Around 80% of the muscle fibres of
marathon runners are aerobic, while in non-athletes the percentage
is typically 30-40%. This is probably partly due to genetics and
partly due to training.
Ditching the switch
Johnson and his colleagues created endurance mice by taking a
slightly different tack. They engineered mice to lack a gene called
HIF-1alpha that is thought to switch muscles from aerobic to
anaerobic activity when oxygen is sparse. These mice could run and
swim like champions as well, reports the team in PLoS Biology.
Johnson's team found hints that the mice are churning out less
lactic acid, a by-product of anaerobic metabolism commonly thought
to cause fatigue, and are clearing it out of their system faster.
Again, this has parallels with long-distance runners, who are
thought to turn over lactic acid more quickly.
But in this case, the animals' athletic feats came at a high price:
after four days of extensive exercise, their performance flagged and
their muscles showed signs of damage. This may have been because
by-products of aerobic metabolism, such as free radicals, had built
up to poisonous levels, Johnson speculates.
Gene doping threat
With the Olympics in full swing, the studies raise the prospect that
athletes and coaches might use drugs or 'gene doping' to mimic the
effects of the genetic engineering and increase their endurance
levels. "Athletes will pick up on this right away," predicts Booth.
"I know it's going to happen."
Evans has already shown that molecules that block another gene,
called PPARalpha, increase muscle capacity in mice and stop them
gaining weight. He hopes that such chemicals, which are already
being put through clinical trials to test whether they lower blood
fat levels, might find a use in fighting obesity. But Evans
acknowledges that athletes would clamour for them too.
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[Definitie:] "An ergogenic aid is any substance or phenomenon that enhances performance."
(Wilmore and Costill) 
