Regulation of muscle growth by multiple ligands signaling through activin type II receptors.
Myostatin is a secreted protein that normally functions as a negative regulator of muscle growth. Agents capable of blocking the myostatin signaling pathway could have important applications for treating human muscle degenerative diseases as well as for enhancing livestock production. Here we describe a potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), which can cause dramatic increases in muscle mass (up to 60% in 2 weeks) when injected into wild-type mice. Furthermore, we show that the effect of the soluble receptor is attenuated but not eliminated in Mstn(-/-) mice, suggesting that at least one other ligand in addition to myostatin normally functions to limit muscle growth. Finally, we provide genetic evidence that these ligands signal through both activin type II receptors, ACVR2 and ACVR2B, to regulate muscle growth in vivo.
Lee
Se-Jin
SJ
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. sjlee@jhmi.edu
Reed
Lori A
LA
Davies
Monique V
MV
Girgenrath
Stefan
S
Goad
Mary E P
ME
Tomkinson
Kathy N
KN
Wright
Jill F
JF
Barker
Christopher
C
Ehrmantraut
Gregory
G
Holmstrom
James
J
Trowell
Betty
B
Gertz
Barry
B
Jiang
Man-Shiow
MS
Sebald
Suzanne M
SM
Matzuk
Martin
M
Li
En
E
Liang
Li-Fang
LF
Quattlebaum
Edwin
E
Stotish
Ronald L
RL
Wolfman
Neil M
NM
D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development*; D055435:Myostatin; D009929:Organ Size; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
D008024:Ligands; C525911:MSTN protein, human; C525912:Mstn protein, mouse; D055435:Myostatin; D016212:Transforming Growth Factor beta; D030301:Activin Receptors, Type II