Pumped Up and Disease-Free: Double the muscle lets mice conquer obesity and diabetes (Diabetes; Muscle)
Authors: Beckman Mary 
Published: August 2003

Like a thirsty sponge, extra muscle might soak up excess sugar floating in the bloodstreams of diabetics. In new research, mice genetically primed to be obese and diabetic instead grow up brawny, hale, and hearty thanks to a second mutation that increases muscle mass. Tinkering with the muscle-regulating gene's product, the study suggests, might help combat obesity and type II diabetes, unhealthy conditions that plague the elderly.

Researchers don't know what causes type II diabetes, but obesity puts people at high risk of acquiring the disease. Diabetics have trouble driving sugar from their blood into muscles and other tissue. Current treatments either reduce the amount of sugar that enters the bloodstream or increase blood concentrations of the hormone insulin, which escorts sugar into cells. After a while, though, muscle cells bar their doors and become insulin-resistant. The need for a better treatment is growing as the population of developed countries ages and puts on diabetes-inducing pounds.

To find out whether extra muscles can counteract diabetes, McPherron and colleagues studied a strain of mice that make twice as much muscle as normal mice do. A gene called
myostatin
that inhibits muscle growth is deleted in these animals, granting them bodybuilder physiques. The tiny Mr. Universes weigh about the same as their normal counterparts do because the increase in muscle is balanced by a lack of fat. To determine why, the researchers examined food intake, body temperature, and metabolic rate, all of which were the same as for normal mice. These results suggested that fat isn't lost to an overactive metabolism or decreased appetite, but that deletion of the
myostatin
gene directs calories into muscle. The researchers then bred the mighty mice to two strains of obese mice, whose mutations lead to overeating, obesity, and insulin-resistant diabetes as the animals age.

The double-mutant offspring of these oddball pairings flaunted twice as much muscle as do either normal mice or mice with either of the obesity-inducing mutations. And they were lean as well as strong: The fat tissue in double mutants weighed less than half that in obese animals. To test whether this body shape protected against diabetes, the team measured the amount of glucose and insulin in the animals' bloodstreams. As expected, the blood of the obese mice had higher-than-normal concentrations of both molecules. In contrast, animals with both the obesity and the muscle-building mutations had healthy amounts. The results don't establish whether it's lost fat or gained muscle that wards off diabetes, but co-author Se-Jin Lee, a molecular biologist at Johns Hopkins University School of Medicine in Baltimore, Maryland, suggests that muscle might soak up excess blood sugar and insulin in the diabetes-prone mice. "If you start with a sponge that's twice as big, you should be able to pick up those spills," he says.

According to molecular biologist Nadia Rosenthal of the European Molecular Biology Laboratory's Mouse Biology Programme in Monterotondo, Italy, less fat is a "very typical side effect of increased muscle mass [in mice]." This observation suggests that keeping muscle weight up could fight fat-associated problems in aging animals. In addition, McPherron's results expose
myostatin
as an attractive new target for antidiabetes drugs--a very absorbing prospect.

--Mary Beckman

A. C. McPherron and S.-J. Lee, Suppression of body fat accumulation in myostatin-deficient mice.
J. Clin. Invest.
109
, 595-601 (2002).
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