Researchers Engineer a Mightier Mouse

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.

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.