Drugs to bulk up muscles may make injuries more likely

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Drugs to bulk up muscles may make injuries more likely

Animal study raises doubts about one approach to treating muscular

dystrophy

http://www.eurekalert.org/pub_releases/2008-01/uomh-dtb012208.php

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 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, 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.

In addition to Faulkner and Mendias, U-M biology student Konstantin

I. Bakhurin also authored the study.

Citation: Proceedings of the National Academy of Sciences, Jan. 8

(pp. 388-393, Issue 1, Volume 105)