BioWorld International Correspondent

LONDON - A study has pinpointed a mammalian gene that controls muscle cell growth but not cell proliferation.

The discovery could make it possible to develop therapies to stimulate increase in body mass without triggering uncontrolled cell division, which might lead to cancer. Patients with muscle-wasting diseases, such as diabetes, AIDS and cancer, could benefit.

Likewise, the knowledge that an independent switch for cell proliferation exists in that molecular pathway could point researchers toward ways to turn off unwanted cell division.

Mario Pende, team leader of the young investigators' program Avenir, at Inserm in Paris, told BioWorld International: "Working on mammalian muscle cells, we demonstrated that this gene allows the cells to grow but does not have any effect on cell proliferation. It may be possible for the pharmaceutical industry to find a drug that can selectively stimulate this pathway."

The work is reported in the Feb. 20, 2005, Nature Cell Biology in a paper titled "Atrophy of S6K1-/- skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control."

Athletes are not the only ones wanting to boost muscle mass. Patients confined to bed for a long period following surgery, the elderly and those with wasting diseases can suffer muscle loss. Death might even result directly from failure of the respiratory muscles.

When an organism grows, two processes are normally involved: an increase in the number of cells, and an increase in the size of the cells. The anabolic factors used by athletes to make their muscles grow bigger stimulate both processes - and the fear is that the excess cell division that results could cause cancer.

In yeast, studies have proved that the cells need to reach a certain size in order to divide. But research in mammalian cells, using different model systems, produced conflicting results: Some studies appeared to show that cells can divide even if they have not grown to a certain minimum size.

Pende and his colleagues set out to discover if the mechanisms regulating cell growth and cell division were independent of each other in mammals, or if they were coordinated in some way.

Previous research had shown that the protein kinase mTOR played a key role in regulating muscle growth and development. The mTOR pathway is an evolutionarily ancient pathway that is conserved from yeast through to mammals.

Pende and his team focused on two further protein kinases, S6K1 and S6K2, which are known to be substrates of mTOR.

Studies of mice lacking one or both of those protein kinases led them to investigate the role of S6K1 in more detail. They found that mice lacking a functional copy of S6K1 had reduced muscle mass. Those animals had a 20 percent reduction in the size of the muscle fibers in the main leg muscle, but the same number of fibers as those in wild-type animals.

Additional experiments showed that the only apparent abnormality in muscles lacking S6K1 was impaired growth.

S6K1 is known to respond to high levels of insulin, insulin-like growth factors and various nutrients, such as amino acids and glucose. Depending on the availability of those anabolic factors, S6K1 coordinates the growth of cells in tissue.

Pende said: "We have shown that animals that do not have the gene for S6K1 are unable to grow even if they are being fed on a protein-rich diet that would normally increase the size of their muscles."

Although the team worked on muscle cells, Pende said the findings can be applied to other tissues, too, including adipose tissue.

The factor that regulates cell proliferation in that pathway remains unknown.

Pende and his colleagues now are planning to carry out studies to help them understand why the cells of animals lacking S6K1 are small.

"Is it because there is a defect in protein synthesis," he asked, "or is there a defect in energy production? These are the two main hypotheses we are working on. We want to find out if S6K1 affects protein synthesis directly, through translational regulation. But if lack of S6K1 affects energy production, then we know that all the anabolic processes that require ATP will be affected."