Myostatin inhibitors may make injuries more likely

Block the action of a protein that normally regulates muscle mass, and watch your muscles grow.

That may sound like a good idea to people with muscle-wasting diseases such as muscular dystrophy, and to older people, whose muscles naturally get smaller and weaker with age. Drugs that restrict the protein myostatin, which normally prevents muscles from being overly bulky, are currently under study, but not on the market, for some medical conditions.

Such drugs, called myostatin inhibitors, also are stirring interest among body builders and athletes. There are already signs of a nascent black market for what might become another illegal performance-enhancing drug in organized sports.

Now, a new University of Michigan study in mice suggests that while myostatin inhibitors may indeed bulk up muscles, they may also bring a troubling side effect – small, brittle tendons that could make muscle injuries more likely.

“Those interested in myostatin inhibitors need to be aware of the fact that by doing these things to muscles, they may be having negative effects on tendons,” says John A. Faulkner, Ph.D., the study's senior author and professor in the Department of Molecular and Integrative Physiology at the U-M Medical School. He is also a research professor at the U-M Institute of Gerontology and professor of biomedical engineering at the U-M College of Engineering. The study results appear in the Jan. 8 print issue of the Proceedings of the National Academy of Sciences.

When you lift weights at the gym, muscle tissue gets damaged. That sets off the release of myostatin, starting a process that clears away damaged proteins and sets the stage for muscle rebuilding, says the study's first author, Christopher L. Mendias, Ph.D. The study suggests we need normal myostatin action for other reasons, too.

“It also appears to make tendons bigger and more flexible,” says Mendias, a U-M post-doctoral research fellow in the Regenerative Sciences Training Program in the Department of Surgery at the U-M Medical School.

It is known that blocking myostatin's activity increases muscle mass and strength, but also makes muscle fibers more vulnerable to injury. The U-M team broke new ground by asking if myostatin also affected the make-up and performance of tendons, the fibrous, tough tissues that connect muscle to bone.

Tendons are stiffer than muscles to begin with, and get stiffer with age. If tendons are brittle and short, as they were in myostatin-lacking mice in the study, they can't adequately do their important job of buffering against muscle injuries.

“The tendon acts like a spring,” Faulkner says, to reduce some of the force on the muscle in a lengthening contraction. Contraction-induced injury is the most common way we injure our muscles. This type of injury already occurs frequently in people with muscular dystrophy – so short, brittle tendons could aggravate the problem if myostatin inhibitors turn out to cause the effect in people.

The research team conducted a series of studies using a strain of laboratory mice that lacked the ability to produce myostatin. They tested the mechanical properties of tendons, compared to tendons in a strain of normal laboratory mice. They isolated and treated tendon cells with myostatin and examined what genes control tendon activity. They were able to identify tendon genes that respond to myostatin, which is produced in muscles, showing that myostatin acts as a hormone to promote strong, flexible tendons.

The findings in mice that lack myostatin are very preliminary and will need to be tested in other mouse strains before seeing if they hold true in people, the researchers say. It's also necessary to explore whether tendon brittleness is a problem if myostatin is merely reduced.

In the meantime, the results are intriguing and cautionary for the variety of people interested in the potential of myostatin inhibitors to increase muscle mass.

For people with the most common forms of muscular dystrophy as well as muscle-wasting diseases, myostatin inhibitors represent one potentially effective type of treatment that is being explored. These inhibitors may be able to reverse the loss of muscle mass and also lessen fibrosis, a build-up of connective tissue in muscle that afflicts people with muscular dystrophy and can be a problem in aging and inactivity. One myostatin inhibitor is currently being tested in people as a possible treatment for Duchenne muscular dystrophy, a debilitating disease that affects one in 3,500 boys worldwide.

For certain types of competitive athletes, the possibility that tendons become stiffer with myostatin inhibitors may not seem a disadvantage, says Mendias, who is also an athletic trainer. The prospect of widespread interest in myostatin inhibitors for enhancing performance, which like steroid use is illegal, is very real, he says, adding that the study results point to a greater need for a system to detect their use.