Mar. 1, 2002 For mice genetically altered to get fat, knocking out a particular gene keeps them both leaner and healthier, Johns Hopkins School of Medicine scientists report in the March 1 issue of the Journal of Clinical Investigation.
That "lean" gene is the blueprint for myostatin, a protein known to limit muscle growth, they report. Previous Hopkins studies found that mice without myostatin are muscle-bound "mighty mice." Now the scientists show that mice without the protein, even mice that usually become obese, gain much less fat as they age.
"This tells me that myostatin might be a useful target for preventing or treating obesity and associated conditions, like diabetes," says Se Jin Lee, M.D., Ph.D., professor of molecular biology and genetics in the school's Institute for Basic Biomedical Sciences. "However, we've been studying genetic knock-outs; we don't know yet whether we can block myostatin in adult animals and see similar effects. In fact, myostatin-blocking agents still need to be developed."
In their experiments, Lee and postdoctoral fellow Alexandra McPherron crossed myostatin-free mice with each of two kinds of obese mice to get "doubly engineered" offspring. These second- generation mice lack myostatin and also have a genetic change that causes obesity. One line of fat mice, officially named "obese," eat excessively because they lack the hormone leptin. The other fat mice eat too much because their production of a protein called "agouti" is abnormal.
By examining amounts of fat and muscle in mice, the scientists discovered that regular and obese mice without myostatin gained less fat as they got older, even though they ate about the same amounts of food as other mice. In fact, "mighty mice" outweigh their counterparts when young, but by 10 months of age or so weighed the same or less than other mice, which had bulked up with fat.
"Some normal mice put on a lot of fat as they age and others not as much, but animals lacking myostatin don't put on much fat at all," says Lee.
By the time they reached middle age at 10 months, mice lacking myostatin had 70 percent less fat (by weight) than regular mice. Among "agouti" mice, myostatin-free animals had about half the fat as others, while the "obese" mice without myostatin had roughly two-thirds the fat of their myostatin-producing counterparts, the scientists report.
The myostatin-free mice were also healthier than their myostatin-producing, engineered-to-be-obese relatives, the scientists report. Both the "obese" and "agouti" mice are models of type 2, or "adult onset," diabetes because they develop the disease's major symptom -- resistance to the hormone insulin. "Mighty" versions of these animals did not, Lee and McPherron report.
They suggest that mice without myostatin, in addition to having less fat, may have enough extra muscle mass to make up for decreasing sensitivity to insulin as they gain weight. In type 2 diabetes, tissues, especially muscle, stop responding to insulin and hence don't soak up sugar from the blood.
Uncontrolled type 2 diabetes can lead to blindness, amputation and death. An estimated 16 million Americans have this form of diabetes, which is an emerging problem in children. Roughly one-third of people with diabetes do not know it, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Most current treatment strategies for diabetes target the insulin pathway, says Lee. Some treatments try to increase insulin production by the pancreas or improve sensitivity to insulin in certain tissues. Other treatments try to keep sugar out of the blood by decreasing its production by the liver or reducing its absorption by the gut.
"Our work shows an alternative approach might be to increase muscle mass, which may make the body more efficient at taking up sugar from the blood," says Lee.
Indeed, in August 2001, NIDDK released results of the Diabetes Prevention Program, which evaluated whether type 2 diabetes could be prevented in people at high risk. Results showed that healthy eating and daily exercise reduced participants' risk by 58 percent, an even bigger drop than with medicine.
Myostatin may also be a good target for agricultural applications, since blocking the activity of myostatin might increase the efficiency of meat production and decrease the fat content of the meat, Lee says.
### The study was funded by the National Institutes of Health and a grant from American Home Products. Myostatin is licensed by Johns Hopkins University to MetaMorphix Inc., and sublicensed to American Home Products. Under a licensing agreement between MetaMorphix and The Johns Hopkins University, Lee and McPherron are entitled to a share of royalty received by the University on sales of products embodying this technology. Lee, McPherron and the University own MetaMorphix stock, which is subject to certain restrictions under University policy. Lee also is a paid consultant to MetaMorphix. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.
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