Looking Beyond Myostatin Blocking

The myostatin protein, known to limit muscle growth, probably works in at least two distinct pathways, and it doesn’t work alone, says Se-Jin Lee at Johns Hopkins University in Baltimore in the Aug. 29 PLoS One.

Myostatin has been a target of molecular biologists seeking to increase or preserve muscle in the face of degenerative diseases like muscular dystrophy.

Lee, who had MDA support for this study, says myostatin appears to regulate local growth of muscle in response to specific events, such as injury, and he speculates that it may also regulate the overall balance between fat and muscle in the body in response to general conditions, such as nutritional status.

His findings suggest that local control of muscle growth may be achieved through regulating how much myostatin is activated in a particular location at any given time and that global control may depend on how much myostatin is circulating in the bloodstream.

In addition, Lee says, his studies demonstrate that at least three proteins contribute to regulation of muscle mass in mice: myostatin, which limits muscle fiber growth, in addition to follistatin and follistatin-related protein, which work against myostatin to promote muscle fiber growth.

Mice with extra follistatin genes and no myostatin genes had four times the normal amount of muscle mass. (Mice lacking myostatin genes with the normal amount of follistatin have twice the normal amount of muscle.)

Understanding all the factors involved in the number and size of muscle fibers is essential to developing optimum treatments, Lee says.

“The studies presented here demonstrate that the capacity for promoting muscle growth by targeting this general signaling pathway is far greater than previously appreciated,” Lee writes, noting that most efforts in this regard have focused on inhibiting myostatin’s activity alone.

“The finding that myostatin is not the sole regulator of muscle mass in mice raises the question as to whether targeting myostatin alone will be the most effective strategy for manipulating this signaling pathway in humans.”