Exercise Pill is No Replacement for Actual Exercise
Says Expert on ‘Inactivity’
Many benefits of exercise were not tested in recent
"exercise pill" study
Read the news on the "Exercise Pill"
from the Salk Institute below this story.
Aug. 5, 2008 – The “exercise pill” hyped by a
report from researchers at the Salk Institute of Biological Studies
cannot be considered a replacement for exercise, says Frank Booth, a
University of Missouri expert on the science of inactivity. He says the
study focused on biology and its relation to health, but did not test
all the commonly known benefits of exercise.
The report by researchers at the Salk Institute for
Biological Studies (Read below) was published in the journal Cell on the
results of a substance that increased exercise endurance without daily
exertion when tested in mice. Media reports described this substance as
an “exercise pill,” potentially eliminating the need for exercise.
In the Cell paper “Exercise Mimetics” the
researchers demonstrated that AMPK-PPARδ pathways, which is a cellular
messenger system, can be targeted by orally active drugs to enhance
training adaptation or even to increase endurance without exercise.
However, Booth cautions that some of the commonly
known benefits of exercise were not tested in the Cell paper including:
• Decreased resting and submaximal exercise heart
rate
• Increased heart stroke volume at all exercise work loads
• Increased maximal exercise cardiac output
• Lower blood pressure and arterial stiffness
• Increased aerobic capacity
A complete list of the 26 benefits not tested in
the paper is included below.
The prevention of the increased risk of chronic
disease produced by lifelong physical inactivity also was not tested in
the Cell paper. According to Katzmarzyk & Janssen (Can J Appl Physiol
29:90, 2004), human physical activity decreases the risk of:
• Coronary artery disease (decreases risk by 45
percent)
• Stroke (decreases risk by 60 percent)
• Hypertension (decreases risk by 30 percent)
• Colon cancer (decreases risk by 41 percent)
• Breast cancer (decreases risk by 30 percent)
• Type 2 diabetes (decreases risk by 50 percent)
• Osteoporosis (decreases risk by 59 percent)
Until targeting AMPK-PPARδ pathways by drugs is
shown to have all the above listed exercise benefits in humans, it is
premature to use the term “exercise mimetics” from the very limited
observations of the Cell paper, Booth said.
Booth’s expectation, based upon his more than 40
years of research experience in exercise and physical inactivity
adaptations, is that the drugs in the Cell paper will only partially
imitate exercise. In order for any “exercise pill” to counter physical
inactivity, the pill must be
polygenic, or control many genes at once; therefore the Cell drugs are
not likely to provide all of the
benefits of comprehensive physical activity. In Booth’s opinion, the
drugs used in the Cell paper were not conclusively proven to mimic
exercise, contrary to media reports.
Booth has more than 40 years of research experience
in physiological, biochemical, molecular and genetic adaptations that
occur during exercise. He is a professor in the MU College of
Veterinary Medicine and the MU School of Medicine and a research
investigator in the Dalton Cardiovascular Research Center. He is a
member of the editorial boards of Journal of Applied Physiology,
American Journal of Physiology: Cell Physiology, Physiological Genomics
and CardioMetabolic Syndrome.
Commonly known benefits of exercise not tested in
the Cell paper were:
• Decreased resting and submaximal exercise heart rate
• Increased heart stroke volume at all exercise work loads
• Increased maximal exercise cardiac output
• Lower blood pressure and arterial stiffness
• Increased aerobic capacity
• Increased strength and cross-sectional area of skeletal muscle
• Delayed loss of muscle mass and strength with aging and physical
frailty
• Improved balance and coordination
• Improved flexibility
• Reduced osteoporosis
• Reduced joint stress and back pain
• Decreased gallstone disease
• Improved endothelial function
• Decreased incidence of myocardial ischemia
• Less myocardial damage from ischemia
• Decreased oxidative stress
• Decreased inflammation
• Improved immune function
• Decreased liver steatosis and fatty liver disease
• Improved insulin sensitivity and reduced risk of type 2 diabetes
• Less likelihood of depression, anxiety, stress and poor
psychological well-being
• Ameliorating hyperlipidemia: lower total cholesterol, higher HDL,
and decreased blood triglycerides
• Improved cognitive function in the elderly
• Increased blood flow and neurogenesis in the dentate gyrus of the
hypothalamus
• Prevention of the loss of brain volume in the elderly
• Delay in decline of physiological reserve in organ systems with
aging
Exercise in a Pill is Very Appealing to Senior
Citizens with Aches and Pains
The following news release was issued by Salk
Institute for Biological Studies
July 31, 2008 - Trying to reap the health benefits
of exercise? It is a challenge for senior citizens suffering from the
aches and pains that come with aging. Forget treadmills and spin
classes, researchers at the Salk Institute for Biological Studies may
have found a way around the sweat and pain. They identified two
signaling pathways that are activated in response to exercise and
converge to dramatically increase endurance.
The team of scientists, led by Howard Hughes
Medical Investigator Ronald M. Evans, Ph.D., a professor in the Salk
Institute's Gene Expression Laboratory report in the July 31 advance
online edition of the journal Cell that simultaneously triggering both
pathways with oral drugs turned laboratory mice into long-distance
runners and conferred many of exercise's other benefits.
In addition to their allure for endurance athletes,
drugs that mimic the effects of exercise have therapeutic potential in
treating certain muscle diseases, such as wasting and frailty, hospital
patients unable to exercise, veterans and others with disabilities as
well as obesity and a slew of associated metabolic disorders where
exercise is known to be beneficial.
Previous work with genetically engineered mice in
the Evans lab had revealed that permanently activating a genetic switch
known as PPAR delta turned mice into indefatigable marathon runners. In
addition to their super-endurance, the altered mice were resistant to
weight gain, even when fed a high-fat diet that caused obesity in
ordinary mice. On top of their lean and mean physique, their response to
insulin improved, lowering levels of circulating glucose.
"We wanted to know whether a drug specific for PPAR
delta would have the same beneficial effects," says Evans. "Genetic
engineering in humans, commonly known as gene doping when mentioned in
connection with athletic performance, is certainly feasible but very
impractical."
An investigational drug, identified only as GW1516
(and not commercially available), fit the bill. When postdoctoral
researcher and lead author Vihang A. Narkar, Ph.D., fed the substance to
laboratory mice over a period of four weeks, the researchers were in for
a surprise.
"We got the expected benefits in lowering fatty
acids and blood glucose levels but no effect, absolutely none, on
exercise performance," says Narkar. Undeterred, he put mice treated with
GW1516 on a regular exercise regimen and every day had them run up to 50
minutes on a treadmill.
Now the exact same drug that had shown no effect in
sedentary animals improved endurance by 77 percent over exercise alone
and increased the portion of "non-fatiguing" or "slow twitch" muscle
fibers by 38 percent. The result, while very dramatic, gave rise to a
vexing question: Why is exercise so important?
First and foremost, exercise depletes muscles'
energy store, a chemical known as ATP. In times of high demand, ATP
releases all its energy and forms AMP. Rising AMP levels alert AMPK, a
metabolic master regulator, which acts like a gas gauge that the cell is
running on empty and revs up the production of ATP. "That led us to
consider whether AMPK activation was the critical trigger that allowed
PPAR delta to work," recalls Narkar.
Usually, AMPK can be found in the cytoplasm, the
compartment that surrounds the nucleus, but the Salk researchers'
experiment revealed that some exercise-activated AMPK molecules slip
into the nucleus. There they physically interact with PPAR delta and
increase its ability to turn on the genetic network that increases
endurance.
"It essentially puts a turbo charge on PPAR delta,
which explains why exercise is so important," says Evans.
Then came the ultimate couch potato experiment. The
researchers fed untrained mice AICAR, a synthetic AMP analog that
directly activates AMPK. After only four weeks and without any prior
training, these mice got up and ran 44 percent longer than untreated,
untrained mice. "That's as much improvement as we get with regular
exercise," says Narkar.
"Exercise in a pill" might sound tempting to couch
potatoes and Olympic contenders alike, but the dreams of the latter
might be cut short. Evans developed a test that can readily detect
GW1516 and its metabolites as well as AICAR in blood and urine and is
already working with officials at the World Anti-Doping Association, who
are racing to have a test in place in time for this year's Summer
Olympics.
Editor’s Notes:
The study was supported by the Howard Hughes
Medical Institute, the Hillblom Foundation and the National Institute of
Health.
Researchers who contributed to the work include
postdoctoral researchers Michael Downes, Ph.D., Ruth T. Yu, Ph.D.,
doctoral candidate Emi Embler, B.S., research associates Michael C.
Nelson, B.S., Yuhua Zou, M.S., Ester Banayo, and Henry Juguilon, in the
Gene Expression Laboratory, doctoral candidate M. Mihaylova, and
assistant professor Reuben Shaw, Ph.D., in the Molecular and Cell
Biology Laboratory, assistant professor Yong-Xu Wang, Ph.D., at the
University of Massachusetts Medical School, Massachusetts, and professor
Heonjoon Kang, Ph.D., at the School of Earth and Environmental Sciences,
Seoul National University, South Korea.
The Salk Institute for Biological Studies in La
Jolla, California, is an independent nonprofit organization dedicated to
fundamental discoveries in the life sciences, the improvement of human
health and the training of future generations of researchers. Jonas
Salk, M.D., whose polio vaccine all but eradicated the crippling disease
poliomyelitis in 1955, opened the Institute in 1965 with a gift of land
from the City of San Diego and the financial support of the March of
Dimes.
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