Mice that grow larger muscles and can run for twice as long as their
unaltered littermates before tiring could point toward new treatments
for the muscle loss that can occur with aging.
Svelte mice: Animals that lack a molecule called NCOR in their
fat cells (bottom) show fewer signs of inflammation (light blue) than
their normal counterparts (top).
The mice were engineered to lack a molecule called NCOR in their
muscle tissue. In a second, related study, knocking out the same
molecule in fat resulted in mice that were overweight but sensitive to
insulin, a result that could lead to more targeted treatments for
diabetes. Both studies were published in the journal Cell last week.
NCOR acts as a dimmer switch for other molecules in a cell. It is
known as a corepressor, slowing the production of transcription factors,
which in turn regulate the expression of genes. Dimmer-switch molecules
are often good drug targets thanks to this subtle effect, says Johan Auwerx,
a researcher at École Polytechnique Fédérale de Lausanne, who led the
first study, which involved knocking out NCOR in muscle. "That's better
from a medical standpoint, because you don't want to turn a molecule all
on or off," he says.
Because NCOR acts on different molecules in many parts of the body,
Auwerx and others have been using genetic techniques to create mice that
lack the protein in only certain types of tissue. Knocking out the
molecule in all tissues from birth is lethal.
According to the second study, eliminating the molecule in fat had a
very specific effect: fat cells became more sensitive to insulin, as did
cells in the muscle and the liver. Insulin resistance is one of the
hallmarks of metabolic syndrome, a precursor to type 2 diabetes, so the
findings could inform drug development for the disease.
"The results suggest that adipose is the organizing tissue for
metabolic syndrome," says Jerrold Olefsky, a researcher at the
University of California, San Diego, who led the second study. "If you
can treat it, you get systemic effects on other tissues."
On a molecular level, knocking out NCOR appeared to mimic the effect
of a class of diabetes drugs known as thiazolidinediones, or TZDs.
These drugs target the same molecule as NCOR, but have significant side
effects, including hepatitis, liver failure, water retention, and heart
failure. Some have been pulled from the market.
The researchers did not see any of these ill effects in the mice,
suggesting that if you target treatment to adipose tissue, "you get rid
of unwanted side effects," says Olefsky. "Targeting NCOR is better
because it has a much more selective role."
Olefsky's team also identified more than 100 genes that are activated
by deleting NCOR in fat. They're now studying these genes as potential
drug targets.
The mice that lacked NCOR in their muscles had a different
outcome—their muscles had many more mitochondria, the fuel source of the
cell, which allowed them to run longer. "That means better capacity to
keep energy levels up," says Auwerx. The researchers knocked out the
same gene in the muscle tissue of worms, which also grew larger muscles,
suggesting that the same trick should work in other animals.
Auwerx is now looking for drugs that can modulate NCOR
levels. Fasting brings levels down, while glucose pushes it up. The
results could be useful in treating aging-related muscle loss, which
occurs even in old people who exercise, as well as diseases such as
muscular dystrophy.
By Emily Singer
From Technology Review
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