|Molecular Pathway in Muscle Helps Explain Effectiveness
of Diabetes Interventions
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
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
of 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 the NIAMS’ Laboratory of Muscle Stem Cells
and Gene Regulation, visit the NIAMS Web site at http://www.niams.nih.gov/Research/Ongoing_Research/Branch_Lab/
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.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Fulco M., et al. Glucose restriction inhibits skeletal myoblast
differentiation by activating SIRT1 through AMPK-mediated regulation
of Nampt. Developmental Cell 14, 661-673, May 2008.