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 the new study by Se-Jin Lee, appearing Aug.
29 in 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, a professor of molecular biology and
genetics in the School of Medicine, 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 were
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 that 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,"
Lee said. "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 currently being tested in a muscular
dystrophy clinical trial, have been designed to
block only myostatin and not other related proteins.
The research was funded by grants from the National
Institutes of Health and the Muscular
Dystrophy Association and by a gift from Merck Research
Laboratories.
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