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RESEARCH BRIEFS
Regulator of Muscle Wasting RevealedAfter a long and weightless flight to Mars, space explorers might have more to contend with than just a barren, inhospitable planet. Due to the severe muscle wasting that occurs in low gravity, most experts predict that by the time the intrepid astronauts reached their destination, they would not even have the strength to unlock the hatch, much less get out and take a stroll around.The process by which muscles wither away in low gravity is the same one that drives wasting in cancer, AIDS, diabetes, fasting, and even extended bed rest. A group of HMS researchers has narrowed down the pathway of gene regulation that leads to muscle wasting in a variety of diseases, and their discovery may stimulate anew the search for therapies to block muscle loss.
Muscle wasting occurs when the rate of protein degradation exceeds the rate of production in muscle cells. Several years ago, Goldberg's group identified a gene whose expression went way up during muscle loss. They dubbed it atrogin-1 because it promoted muscle atrophy. The gene turned out to encode an enzyme that speeds the destruction of cellular proteins by adding ubiquitin molecules to them and shuttling them into the ubiquitin-dependent protein degradation machinery. Marco Sandri, a postdoctoral fellow in Goldberg's lab, led the effort to pinpoint the control mechanism of atrogin-1 expression in collaboration with Stewart Lecker, HMS assistant professor of medicine at Beth Israel Deaconess Medical Center. Their results show that the chief regulators of atrogin-1 are the Forkhead box O (FOXO) family of transcriptional regulators. When the researchers introduced the gene for activated FOXO3 into the leg muscles of adult mice, they could see the muscle fibers that expressed FOXO3 became withered, while neighboring fibers that did not make this protein remained plump and healthy. When the researchers blocked FOXO3 activation, the muscle wasting induced by stress hormones was greatly reduced. In other types of cell, FOXO3's best known role is to regulate cell death (see related brief, "Sirtuin..."). But during muscle atrophy, FOXO acts a little differently. Muscle cells do not actually die when FOXO is activated, they just get smaller as more and more proteins are destroyed. When atrophied muscles encounter natural muscle builders like the hormones insulin or insulin-like growth factor, FOXO3 activity shuts down and rebuilding begins. Inactivating FOXO3 therapeutically should mimic the action of normal muscle growth signals, making FOXO3 an attractive target for new drugs. The FOXO3 work was supported partly by the National Space Biomedical Research Institute, a NASA-sponsored academic consortium whose goal is to solve the problem of muscle loss at zero gravity. But Goldberg sees benefits of the research closer to home. "The space program has glamor, but our primary goal is to help people here on Earth," he said. The work also was supported by the Muscular Dystrophy Association. --Pat McCaffrey
Sirtuin Protein SIRT1 Links Stress with Cell SurvivalWhat doesn't kill you makes you stronger, goes the old saw. Scientists know the saying holds true for lower organisms like yeast and worms. For these creatures, sublethal environmental insults like changes in temperature or food deprivation can extend life span. Genetic studies have shown the sirtuin Sir2 to be indispensable for stress resistance and prolonging life in simple organisms, but the way Sir2 (SIRT1 in mammals) might work has remained a puzzle.Recent studies in cell culture from Michael Greenberg's lab link mammalian SIRT1 and the cell survival pathway governed by the Forkhead family of transcription factors. By regulating Forkhead activity, SIRT1 appears to help cells counter environmental stress. And the action of SIRT1 makes the cells less likely to die by apoptosis, he and his colleagues report in the March 26 Science. "This work makes a connection between two proteins implicated in stress signaling and longevity," said Greenberg, HMS professor of neurology at Children's. "By providing mechanistic evidence for how stress might regulate organism survival, this work has significant implications for understanding organismal aging." Sirtuins are enzymes that modify proteins by removing acetyl groups, but their substrates are mostly unknown. The researchers show that stress causes the addition of these groups to a Forkhead family member, FOXO3. When FOXO3 meets the sirtuin SIRT1 in the cell nucleus, SIRT1 removes the acetyl groups, altering the ability of FOXO3 to regulate genes. "SIRT1 appears to redirect FOXO3 toward genes involved in the stress response and away from genes inducing cell death," explained lead author Anne Brunet, a postdoc in Greenberg's lab when the work was done and now a Stanford assistant professor. With some kinds of stress, though, cell survival may not be the best outcome. If extreme environmental conditions cause heavy damage to the cell's DNA, for example, a cell may need to die to prevent the perpetuation of mutations and the generation of cancers. In this case, the cell would depend on FOXO3 to trigger apoptosis. "It's a matter of having a tightly controlled balance," said Brunet, adding that SIRT1's deacetylation of FOXO3 may be a mechanism of this balance. The ability of SIRT1 to enlist FOXO3 to induce enzymes that protect cells against DNA damage and oxidative stress could underlie the life-extending properties of the sirtuins. But given FOXO3's multiple functions in physiology (see related brief, "Regulator..."), both Greenberg and Brunet emphasize that the relationship between what they have observed in solitary cells and what happens in whole animals will need to be carefully worked out.
Calorie Restriction May Reduce Risk of Breast CancerResearch has shown that eating less can reduce the risk of breast cancer--if you're a mouse. But while caloric restriction may make rodents and worms live longer, healthier lives, no one knows its effects on human health. It is hard to ask the question, since a protocol of starvation is unlikely to pass the human subjects research committee or to be very popular with research volunteers.By investigating a group of more than 7,000 Swedish women who had been hospitalized for anorexia, researchers were able to measure for the first time the effect of severe calorie restriction on breast cancer incidence in women. They concluded that for humans, calorie restriction is associated with decreased odds of getting breast cancer. "We studied women with a considerably reduced calorie intake and found that overall they had half the risk of breast cancer compared with the general population," said Karin Michels, lead author of the study, published in The Journal of the American Medical Association on March 10. Michels is an associate professor of epidemiology at HSPH and of obstetrics, gynecology and reproductive biology at HMS. The biggest decrease in breast cancer risk, 76 percent, was observed for women who had been anorexic, but went on to have a child. Women who never experienced pregnancy had a 23 percent reduction in risk. Michels worked with Anders Ekbom, HSPH adjunct professor of epidemiology, to scrutinize the health records of women who were hospitalized for anorexia in Sweden between 1965 and 1998. The researchers cross-referenced cancer registry records to determine how many women developed breast cancer and fertility records to see whether the women had ever had children. Though diet has been implicated in developing breast cancer, Michels said that studies show no striking correlation with any single dietary component. Her study suggests that total caloric intake may be more important than any particular food or nutrient. "We are not trying to give the message that women should be anorexic," Michels said. "Anorexia nervosa is a severe and life-threatening disease. We are using anorexia as a model to study caloric restriction in women, which we would not be able to do otherwise." According to Michels, because anorexia usually happens early in life (most women in the study were younger than 19 at the time of hospitalization), the study supports the idea that early life experiences may be important to a woman's chance of developing premenopausal breast cancer. --Pat McCaffrey |
