Monday, June 16, 2008

Making Old Muscle Young

Researchers boost growth of muscle stem cells to stop age-related muscle deterioration.

By Jennifer Chu

Restoring youth: Older muscles typically grow new cells slower than young ones do, but inhibiting a key pathway in the stem cells of aging mice appears to restore youthful vigor. In these two images, muscle stem cells are shown in red, and muscle fibers in green. The top image, which shows muscle from older mice given the inhibitory treatment, clearly exhibits more muscle growth than the bottom one, which shows muscle from untreated aging mice. Credit: UC Berkley

Manipulating stem cells in old muscle can restore youth to aging tissue, according to research from the University of California, Berkeley. Scientists altered the activity of a molecular pathway to make stem cells in older tissue produce new muscle fibers at levels comparable to young stem cells. They say that their findings may one day lead to novel therapies for age-related diseases such as Alzheimer's and Parkinson's, as well as possibly to the reversal of the atrophying effect of aging.

"When we exert ourselves, like going to the gym or running after the bus, we always damage muscles which are being replaced over time [by] muscle stem cells," says Irina Conboy, assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center. "But when we get older, cell death is faster than cell replacement."

Muscle wasting--loss of muscle mass--occurs both during aging and in a number of diseases, such as cancer and muscular dystrophy. Because muscle loss often correlates with poor health outcomes, pharmaceutical companies have been striving to find new treatments that boost muscle mass without the harmful side effects of anabolic steroids.

In previous research, Conboy's team found that old stem cells, placed in culture with young blood and muscle tissue, were able to churn out new cells at a speedier rate. Conversely, young stem cells exposed to old tissue grew prematurely old, significantly scaling back new-cell production. Conboy reasoned that stem cells must receive different chemical cues in youth versus in old age, and identifying and manipulating those cues may successfully restore youth to old muscle.

In their current study, published in the online edition of the journal Nature, Conboy and her team found that old muscle produces elevated levels of a molecule called TGF-beta, which is known to inhibit muscle growth. The researchers then showed that the muscle-deteriorating effects of TGF-beta can be reversed by blocking its pathway in old mice.

In the experiments, the researchers used RNA interference, which can silence specific genes, to inhibit the molecules that act downstream of TGF-beta to prevent cells from multiplying. They then locally injured the muscles of treated mice, as well as untreated old and young mice, by injecting a small amount of snake venom, which killed muscle tissue in the immediate vicinity.

After five days, the team found that the young mice were able to produce healthy cells to replace damaged tissue. The treated older mice, whose inhibitory pathways were suppressed, were able to regenerate new cells in much the same way. Not surprisingly, old untreated mice did not recover as well and developed fibroblasts and scar tissue around the injured site.