Harvard scientists have created a mighty mouse, a rodent endowed with a rare type of muscle that combines unusual power and speed, like that of a sprinter, with the endurance of a marathoner. “Damn, they’re good athletes,” said Bruce Spiegelman, a professor of cell biology at Harvard Medical School, shortly after the results were published in Cell Metabolism. The genetically modified mice ran 25 percent longer on a treadmill, and they did so at faster speeds than normal mice, covering nearly 50 percent more ground before reaching exhaustion. Their extraordinary performance comes from a little-known muscle type termed IIX, which normally exists as a few scattered fibers mixed with other, more abundant, muscle-fiber types.
Spiegelman’s interest in his super mice has less to do with their enhanced athletic performance, however, than with the therapeutic potential of being able to control muscle-fiber-type switching. Treatments for diseases of disuse and of wasting, as well as for muscular dystrophies, are what he has in view.
“In mammals, normally, almost all muscles are mixed,” he explains. “We don’t have muscles that are purely one type,” as does the IIX mouse. That means the relative proportion of the various fiber types determines the characteristics of a particular muscle group. Muscles that twitch slowly tend to be more oxidative—favoring endurance activities. Those that twitch fast are typically glycolytic—they rely more on stored carbohydrates, conferring strength and speed. “IIX fibers are the one type that falls off that paradigm,” Spiegelman says. “They are fast, but also oxidative, so they provide the ability to burst energy quickly, but they use oxidative metabolism.”
Possibly, he says, IIX fibers are an intermediate-stage form that exists when muscles are changing in response to training. Though type 1 muscle—the slow-twitch, highly oxidative kind best suited for endurance activity—is probably the best known, “it is not clear in humans that you can do much to change them,” Spiegelman says. Most fiber-type switching in human muscle is from IIB—a fast-twitch muscle adapted for strength and speed—to IIA, an oxidative, slow-twitch fiber that enhances endurance. IIX may be something in between.
In 2002, Spiegelman’s laboratory discovered that increasing the production of a gene called PGC-1α could transform muscles of mixed fiber-type into predominantly slow-twitch types. Turning up a sister gene called PGC-1β created the mighty mouse. “What’s cool is that PGC-1β did something different,” says Spiegelman; that may augur well for future research. In the meantime, he has recently shown that PGC-1α, on which his research has progressed further, “has a fantastic effect” on Duchenne muscular dystrophy in a mouse. “This is exciting,” he explains, because “this is a terrible disease for which there is no treatment. It is 100 percent penetrant, meaning if you have the gene, you get the disease. The mean age of [human] diagnosis is 4.6 years, and the average age at death is 17 years.”
Screening for chemical compounds that will elevate PGC-1α in humans is now under way at the Broad Institute in Cambridge (see “Bigger Biology,” November-December 2006, page 72), under the direction of Loeb professor of chemistry Stuart Schreiber. Because exercise is known to have beneficial effects throughout the body, and the PGC-1 genes are known to be under the control of exercise, there is also reason to believe that they may play important roles in tissues other than muscle—an intriguing possibility that Spiegelman intends to explore during the next few years.
~Jonathan Shaw
Bruce Spiegelman e-mail address: bruce_spiegelman@dfci.harvard.edu
Bruce Spiegelman website: https://cellbio.med.harvard.edu/faculty/spiegelman
