Creating a Hospitable Environment for Muscle Regeneration

Article Highlights:
  • Kathryn Wagner, of Johns Hopkins University School of Medicine and Kennedy Krieger Institute in Baltimore, is studying the effects of inhibiting the muscle-limiting protein myostatin in a mouse model of Duchenne muscular dystrophy (DMD).
  • Wagner's emphasis is on decreasing muscle fibrosis (scar tissue formation), one of the effects of reducing myostatin levels.
  • Wagner says creating a "hospitable environment" in which muscle can regenerate — such as one with less fibrosis — probably will be beneficial in combination with other treatment strategies now in development for muscular dystrophy.
by Margaret Wahl on March 31, 2011 - 11:34am

QUEST Vol. 18, No. 2

In May 1997, Kathryn Wagner was doing something she hadn’t had much time to do in years: She was watching television. Wagner had just given birth to her first baby, James, and was on leave from her postgraduate training in neurology at Johns Hopkins University School of Medicine in Baltimore.

“I distinctly remember that I was on my bed, with my baby, watching Dan Rather on the evening news show pictures of the ‘mighty mouse,’” she recalls, referring to a genetically engineered mouse developed in the laboratory of molecular biologist Se-Jin Lee, who happened to be at Hopkins as well (see Interfering with an Inhibitor of Muscle Growth).

Mighty mouse led to fruitful collaboration

The so-called mighty mouse lacked a protein called myostatin and had extremely large muscles. “I just thought, ‘That has got to be helpful to muscular dystrophy research,’” Wagner recalls.

When she was ready to go back to work, Wagner approached Lee about doing a postdoctoral fellowship in his lab and “we ended up having a fruitful collaboration.”

Wagner had earned a doctorate in neuroscience, as well as a medical doctorate, at Hopkins in 1994. During her training in the laboratory of neuroscientist Richard Huganir, she had identified the gene for a muscle protein called dystrobrevin, located in muscle fibers and associated with the dystrophin protein, known to be absent in Duchenne muscular dystrophy.

“Finding something similar to dystrophin and associated with dystrophin made me read the literature and get very excited about muscle and muscle diseases,” she says, and her career shifted in that direction.

In 2002, with Se-Jin Lee and others, Wagner, by then an MDA research grantee, published a paper showing that loss of the myostatin protein significantly reduced the severity of the Duchenne dystrophy-like disease that develops in mice that lack dystrophin, known as mdx mice.

Wagner cross-bred myostatin null mice (mice that don’t produce myostatin) to mdx mice (mice that don’t produce dystrophin), “and I’ve been working on myostatin inhibition ever since,” she says.

She’s now an associate professor of neurology and neuroscience at Hopkins and the director of the Center for Genetic Muscle Disorders at the Hopkins-associated Kennedy Krieger Institute. MDA has given Wagner two additional research grants, both related to reducing myostatin in muscle tissue.

Far less fibrosis when myostatin was gone

Wagner found that mdx mice that lacked myostatin were stronger and more muscular than their mdx counterparts. But there was something else that got her attention: They had far less fibrosis (scar tissue) in their muscles than one would have expected for dystrophin-deficient mice.

Fibrosis is a process in which normal tissue that sustains damage is replaced by fibrous connective tissue. Cells called fibroblasts (generators of fibrous tissue) are the main actors in this process, producing proteins called collagens.

It’s a natural phenomenon and may have some value in sealing off parts of an organ to keep an infection from spreading, but, like many biological processes, fibrosis can do more harm than good. Once it gets started, Wagner notes, the original function of the tissue can be destroyed.

Not all muscle diseases involve fibrosis, she says, but it’s prominent in DMD and the related Becker muscular dystrophy, as well as several forms of congenital muscular dystrophy. Fibrosis, Wagner speculates, “may create an environment in which muscle stem cells cannot easily replicate or fuse to form muscle fibers. The proteins that fibroblasts secrete are counterproductive to new muscle formation.”

Myostatin, she has found, stimulates fibroblasts, while it suppresses muscle precursor cells called myoblasts. Blocking or removing myostatin does just the opposite: It suppresses fibroblast growth and development, while stimulating myoblasts.

“We actually noticed the antifibrotic effect right from the first experiments in which we cross-bred the mdx mice and the myostatin null mice,” Wagner says. “It was clear there was less fibrosis in the mdx animals lacking myostatin. But at that time, we really didn’t even suspect that myostatin was acting directly on fibroblasts.”

Initially, Wagner says, almost all the excitement about myostatin inhibition focused on the increase in the size of the muscles. But she doesn’t think that’s as important as other things that myostatin inhibition can do.

“I don’t think bigger muscles are necessarily better muscles,” she says. “And I think the field is less interested in muscle size now. In the absence of myostatin, there clearly is improved regeneration. That in and of itself is a good thing, and there’s this additional benefit of less fibrosis, which is potentially wonderful.”

Creating the right environment

Wagner is interested in creating a hospitable environment in which muscle can regenerate, either naturally or with outside help, such as gene therapy, cell transplantation, or other strategies now in development. She believes reducing myostatin levels might even rescue muscle tissue that’s already sustained considerable damage and fibrosis.

“In the mdx mouse, we have a lot of data that myostatin inhibitors can reverse fibrosis, even in very old mdx mice,” she says. “I don’t have any reason to think that wouldn’t happen in humans.”

Your rating: None Average: 4.3 (4 votes)
MDA cannot respond to questions asked in the comments field. For help with questions, contact your local MDA office or clinic or email See comment policy