The Johns Hopkins scientist who first showed that the absence of the protein myostatin leads to oversized muscles in mice and men has now found a second protein, follistatin, whose overproduction in mice lacking myostatin doubles the muscle-building effect.

Results of Se-Jin Lee's new study, appearing on August 29 in the online, open-access journal PLoS ONE, show that while mice that lack the gene that makes myostatin have roughly twice the amount of body muscle as normal, mice without myostatin that also overproduce follistatin have about four times as much muscle as normal mice.

Lee, M.D., Ph.D., a professor of molecular biology and genetics, says that this added muscle increase could significantly boost research efforts to "beef up" livestock or promote muscle growth in patients with muscular dystrophy and other wasting diseases.

Specifically, Lee first discovered that follistatin was capable of blocking myostatin activity in muscle cells grown under lab conditions. When he gave it to normal mice, the rodents bulked up, just as would happen if the myostatin gene in these animals was turned off. He then genetically engineered a mouse that both lacked myostatin and made extra follistatin. If follistatin was increasing muscle growth solely by blocking myostatin, then Lee surmised that follistatin would have no added effect in the absence of myostatin.

"To my surprise and delight, there was an additive effect," said Lee, who notes these muscular mice averaged a 117 percent increase in muscle fiber size and a 73 percent increase in total muscle fibers compared to normal mice.

"These findings show that the capacity for increasing muscle growth by targeting these pathways is much more extensive than we have appreciated," adds Lee. "Now we'll search for other players that cooperate with myostatin, so we can tap the full potential for enhancing muscle growth for clinical applications."

Lee adds that this issue is of particular significance, as most agents targeting this pathway, including one drug being currently tested in a muscular dystrophy clinical trial, have been designed to block only myostatin and not other related proteins. Source : Johns Hopkins Medical Institutions

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Myostatin is a transforming growth factor-ß family member that normally acts to limit skeletal muscle growth. Mice genetically
engineered to lack myostatin activity have about twice the amount of muscle mass throughout the body, and similar effects
are seen in cattle, sheep, dogs, and a human with naturally occurring loss-of-function mutations in the myostatin gene. Hence,
there is considerable interest in developing agents capable of inhibiting myostatin activity for both agricultural and human
therapeutic applications. We previously showed that the myostatin binding protein, follistatin, can induce dramatic increases
in muscle mass when overexpressed as a transgene in mice. In order to determine whether this effect of follistatin results solely
from inhibition of myostatin activity, I analyzed the effect of this transgene in myostatin-null mice. Mstn2/2 mice carrying
a follistatin transgene had about four times the muscle mass of wild type mice, demonstrating the existence of other
regulators of muscle mass with similar activity to myostatin. The greatest effect on muscle mass was observed in offspring of
mothers homozygous for the Mstn mutation, raising the possibility that either myostatin itself or a downstream regulator may
normally be transferred from the maternal to fetal circulations. These findings demonstrate that the capacity for increasing
muscle growth by manipulating TGF-ß signaling pathways is much more extensive than previously appreciated and suggest
that muscle mass may be controlled at least in part by a systemic mode of action of myostatin.
Citation: Lee S-J (2007)