The discovery of the long-sought switch, a molecule called PGC-1, might some day enable physicians to give weakened patients a drug to build up muscular endurance without exercise, say the researchers. Normally, the only way to achieve this muscular reprogramming is through long, demanding training regimens.
Published in the Aug. 15 issue of the journal Nature, the findings describe the pivotal role of PGC-1 in transforming "fast twitch" fibers (Type II) to "slow twitch" fibers (Type I). "Fast twitch" fibers create the bulkier, strong but quickly fatigued muscles of weightlifters or sprinters. Most muscles contain a combination of the two fibers.
"PGC-1 appears to be the switch, or a major component of it, that enables your body's muscles to adjust to the demands being put on them," explains Dana-Farber's Bruce M. Spiegelman, PhD, a cell biologist and the study's senior author. "Understanding how this system works could make it possible to develop a drug to manipulate this system."
The research team included investigators from Dana-Farber, Beth Israel Deaconess Medical Center, Boston, and the University of Texas Southwestern Medical Center, Dallas.
Spiegelman's laboratory had previously shown that PGC-1, a molecule known as a "transcriptional co-activator," acts as a switch in the liver to regulate the manufacture of glucose, which fuels cells.
In the muscle research, PGC-1 was found to have a somewhat similar role: it triggers the development of cellular power plants called mitochondria that give slow-twitch fibers their extraordinary endurance. At the same time, the process turned on by PGC-1 produces proteins such as myoglobin that slow-twitch muscles require.
Spiegelman, Jiandie Lin, PhD, the paper's first author, and their colleagues created transgenic mice that carried the PGC-1 gene in all their skeletal muscles. An added bit of DNA, called a promoter, caused the PGC-1 gene to now be active in Type II muscle fibers as well as Type I fibers.
When the scientists studied the bioengineered mice, they found that the muscles normally rich in Type II fibers now had a characteristically reddish color caused by the conversion of the fibers to oxygen-fueled Type I fibers. Futhermore, an endurance test showed that the muscles that had been treated with the PGC-1 genes contracted efficiently for seven minutes, while muscles from untreated mice worked efficiently only for about two minutes.
PGC-1 is naturally expressed, or active, in skeletal and heart muscle. The researchers found that PGC-1 is expressed at higher levels in muscles containing a lot of Type I fibers. When they looked at fibers that had been exposed to PGC-1, those fibers had more mitochondria and active genes normally in Type I fibers. Type I fibers use the mitochondria and oxygen as a source of energy – as in aerobic exercise. In contrast, Type II, fast-twitch fibers get their energy mainly from the breakdown of sugar.
While the researchers caution they're not promising a new athletic stamina-enhancing drug, they say it's certainly possible that the might benefit people who are deficient in Type I muscle fibers because of medical conditions.
"Down the road, one would like to be able to incorporate it into some therapy where one has diseased muscles," said Rhonda Bassel-Duby, PhD, a molecular biologist at UT Southwestern and a collaborator on the paper. "One possibility is using [a drug] to give people on bed rest more endurance without having to do the exercise," she said.
Spiegelman, who is also a professor of cell biology at Harvard Medical School, adds that these findings in time may benefit people with Type 2 diabetes, as the Type I muscle is more responsive to insulin in regulating blood glucose levels.
The study was funded principally by the National Institutes of Health.
Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Journal
Nature