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Study Could Lead to a Drug That Mimics the Benefits of Exercise

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Duke Health News 919-660-1306

DURHAM, N.C. – Researchers at Duke University Medical Center
and the University of
Texas Southwestern Medical Center
in Dallas have found a
biochemical pathway in muscle cells responsible for generating
many of the beneficial effects of regular exercise.

The discovery identifies targets for the discovery of new
drugs that could improve the quality of life in people
suffering from chronic illness who could benefit from aerobic
exercise, but are unable to perform the amount of exercise
necessary to produce the desired effects, said R.
Sanders Williams, M.D., dean of the Duke University School
of Medicine and senior author of the study that appears in the
April 12, 2002 issue of the journal Science. Drugs that stimulate
this pathway also could reproduce health benefits of exercise
that help to prevent diabetes and cardiovascular disease.

The research was conducted at UT Southwestern where Williams
was director of the Ryburn Center for Molecular Cardiology
until 2001 when he became dean of the School of Medicine at
Duke.

In 1998, Williams and colleagues published findings showing
that activating the signaling protein calcineurin could mimic
some of the effects of endurance exercise. In the new study,
which was funded by grants from the National Institutes of
Health, researchers detail the discovery of another cellular
signaling pathway involving a different class of signaling
proteins called calmodulin-dependent protein kinases (CaMK)
that controls genes that influence the physiological and
metabolic properties of muscles.

"We think this discovery could lead to the synthesis of new
drugs that will allow individuals to acquire the health
benefits of regular exercise, even if they cannot exercise. It
has the potential to improve the lives of patients with heart
failure, pulmonary disease, renal failure, diabetes and other
chronic diseases," Williams said.

Williams and his colleagues have spent 20 years studying why
muscle tissues remodel themselves when subjected to different
forms of exercise. Skeletal muscle fibers consist of two types
-- "slow-twitch" muscle that can handle long-term, low-level
loads, and "fast-twitch" muscle that responds to abrupt heavy
loads. In remodeling, sudden heavy exercise such as
weightlifting makes muscles larger while sustained exercise
such as long-distance running alters the fiber-type composition
of muscle to increase resistance to fatigue and reduce a
person's risk for diabetes or cardiovascular disease.

The scientists set out to answer a central question of
exercise biology: how do muscle cells sense that they are being
exercised and translate that signal into changes in gene
expression that influence the metabolic properties of muscle?
Answers to this question could lead to new drug therapies that
mimic the effects of regular exercise for individuals unable to
exercise, but who need its benefits, Williams said.

In the new study, researchers identified a protein enzyme
called calmodulin-dependent protein kinase (CaMK) that controls
production of mitochondria in mammalian muscle tissue.
Mitochondria are the structures within cells that transform
oxygen and other molecules into energy for all cellular
functions. People who exercise regularly have more
mitochrondria in their muscles than those who are sedentary,
Williams said. The scientists produced genetically altered mice
that produce a continuously active form of CaMK in skeletal
muscles. They found that CaMK triggers a signaling pathway that
controls mitochondrial production in mouse cells, so that the
muscles of sedentary mice assumed the characteristics of
muscles of animals that exercised regularly. They found that
CaMK activates a gene that encodes another protein called
PGC-1, which is known to activate hundreds of genes that
control the amount of mitochondria in a cell.

"Activation of CaMK recapitulated the effects of exercise,
indicating that this is a central pathway by which exercise
modifies the metabolic properties of skeletal muscles,"
Williams said. "Until now, scientists did not suspect that this
particular enzyme was involved in that control."

The findings are clinically significant not only because
skeletal muscles are necessary for movement, but because they
affect metabolism of sugars and fats that circulate in the
blood, Williams said. The metabolic properties of skeletal
muscles will determine one's risk of developing diabetes and
other chronic conditions.

"An inability to exercise complicates many chronic medical
conditions and makes those conditions worse. For example, we
know that heart failure patients who exercise regularly feel
better and over time acquire a greater capacity to exercise,
but many are unable to perform the amount of exercise necessary
to produce the favorable effects. One application of this
discovery, if it leads to the development of drugs to activate
this pathway, would to be help improve the quality of life of
people who have such chronic diseases," he said.

A research team at Duke led by Williams is continuing to
study the pathway described in this study to identify the best
targets for drug discovery. They also seek to determine whether
this pathway is pertinent to other tissues such as fat or even
to the biology of cancer cells, Williams said. Mitochondria are
fundamental to the function of all cells and the pathway that
controls mitochondria could possibly be manipulated in other
kinds of medical conditions, he said.

The study's co-authors include Hai Wu, Shane Kanatous,
Frederick A. Thurmond, Teresa Gallardo, Eiji Isotani and Rhonda
Bassel-Duby, all of the University of Texas
Southwestern Medical Center
.

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