Molecular pathway in muscle helps explain effectiveness of diabetes interventions

May 12 2008

Scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), demonstrate for the first time in a mouse model that skeletal muscle cells cultured in a low-calorie environment refrain from differentiating, an energy-demanding process by which cells mature and specialize.

They also describe for the first time the molecular pathway (the protein-signaling system by which cells read and react to their environment), involving the protein SIRT1 that becomes activated in mouse skeletal muscle cells when they receive fewer calories. The study appears in the May 13 issue of Developmental Cell.

The discovery of this molecular pathway in muscle is also of interest to diabetes researchers because calorie-restriction diets, as well as the drug metformin, are both treatments for type 2 diabetes and a related condition, metabolic syndrome. The treatments help the body better regulate the body's uptake of sugar, a nutrient that people with these conditions have trouble regulating. But the exact mechanism of action of these treatments is unclear.

Vittorio Sartorelli, M.D., chief of the NIAMS' Laboratory of Muscle Stem Cells and Gene Regulation and leader of the research team said, "We think this finding has given us a better molecular understanding of how lifestyle and drug interventions function in the treatment of type 2 diabetes and metabolic syndrome." Skeletal muscle plays a critical role in type 2 diabetes and in a related condition, metabolic syndrome. It is responsible for more than 40 percent o' the body?s uptake of sugar, a nutrient the body has trouble regulating in both conditions.

In their project, Sartorelli and his colleagues set out to investigate the relationship between skeletal muscle cells, calorie restriction, metformin and SIRT1 in mice. They cultured skeletal muscle cells from normal mice in a low-glucose environment to restrict calories and treated others with metformin. As expected, in each intervention the cells failed to mature and form myocytes, cells that are the building blocks of muscle fibers. What was new in their findings, however, was that metformin and calorie restriction both promoted the activation of two proteins, AMPK and Nampt, which in turn made SIRT1 more active and capable of suppressing cell differentiation.

When the scientists tried metformin and calorie restriction in the cells of mice engineered to have inactive SIRT1, the muscle cells ignored the suppressive effects of the interventions and remained able to produce mature myocytes. In addition, the usual changes in gene activity in response to calorie restriction in mice with inactive SIRT1 did not occur, another indication that SIRT1 is necessary to mediate the effects of calorie restriction.

Sartorelli said the team's research shows that SIRT1 is a molecule that allows skeletal muscle to read a low amount of nutrients in the environment and suppress genes that promote cell differentiation, thereby conserving energy. He added that it also demonstrates that two interventions that can control diabetes - reduced caloric intake and metformin - both target SIRT1.

Collaborating institutions in this work included Weill Medical College of Cornell University in New York City, Children's National Medical Center in Washington, D.C., and the Ottawa Health Research Center Institute in Canada.

For more information about diabetes prevention and treatment, visit the National Diabetes Information Clearinghouse of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a part of the NIH, at http://diabetes.niddk.nih.gov/.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.