A genetically engineered 'mighty mouse' is helping Medical College of Georgia researchers find the best way for young people to build bone and avoid osteoporosis.
"We are interested in kids; we want to know how to maximize their bone during peak periods of growth while they still can," says Dr. Mark Hamrick, bone biologist. "One of the best predictors of who is going to get osteoporosis and who is not is how much bone you have at sexual maturity. So we want to know what people can do from zero to age 18 that really is going to pack that bone on." These mighty mice, with up to 70 percent more muscle mass than a regular mouse and essentially no body fat, and a $1 million grant from the National Institutes of Health are helping Dr. Hamrick answer that question. The mice lack the myostatin gene, a negative regulator of muscle mass. "Lots of genes control muscle development," says Dr. Hamrick. "This one is pretty significant in terms of not letting muscles get too big."
Myostatin is expressed at highest levels during development, when the embryo is growing, to ensure that muscles don't overgrow, Dr. Hamrick says. The level expressed changes naturally over the course of life. "It's still expressed as children grow and is present in very low levels in adults," he says. "It's suggested that you might get rises in myostatin levels with aging, which is associated with a loss of muscle mass that typically accompanies increased age. " Some muscle-wasting diseases as well as space flight and extended bed rest also are associated with increased myostatin levels. Numerous products claim to help adults build muscle by turning off this powerful muscle regulator produced by muscle cells, Dr. Hamrick says. But the only product scientifically proven to block myostatin is a monoclonal antibody now under study for its potential to treat muscular dystrophy, he says.
The muscular rodents that result when myostatin is taken out of the equation are enabling scientists to explore the hypothesis that one of the best ways to build bone is to build muscle.
"People have argued for many years that the way to increase bone density and strength is force – bones respond to the stress and strain placed on them by forming more bone – and the best way to increase that force is big muscles," says Dr. Hamrick. "We want to know if that is the case. We want to know if certain genes involved in bone formation are up-regulated with increased muscle and if these genes are stress-responsive genes.
"We also want to know if muscle can affect bone in other ways. Maybe it affects different hormones. Maybe it's a source of different growth factors itself. There's the frequency of a stimulus, not just the magnitude of it. There are also changes in blood and fluid flow that occur. We need to know the real mechanism."
And does it matter if the force put on bone comes from fat rather than muscle? "Some studies suggest that fat is a great predictor of bone mass and that it has protective effects on the bone in postmenopausal women," Dr. Hamrick says. Yet the growing number of obese children in the United States tend to have lower bone mass relative to their body weight than they should, he says.