Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases.
Myostatin is a transforming growth factor beta family member that acts as a negative regulator of skeletal muscle growth. Myostatin circulates in the blood of adult mice in a noncovalently held complex with other proteins, including its propeptide, which maintain the C-terminal dimer in a latent, inactive state. This latent form of myostatin can be activated in vitro by treatment with acid; however, the mechanisms by which latent myostatin is activated in vivo are unknown. Here, we show that members of the bone morphogenetic protein-1/tolloid (BMP-1/TLD) family of metalloproteinases can cleave the myostatin propeptide in this complex and can thereby activate latent myostatin. Furthermore, we show that a mutant form of the propeptide resistant to cleavage by BMP-1/TLD proteinases can cause significant increases in muscle mass when injected into adult mice. These findings raise the possibility that members of the BMP-1/TLD family may be involved in activating latent myostatin in vivo and that molecules capable of inhibiting these proteinases may be effective agents for increasing muscle mass for both human therapeutic and agricultural applications.
Wolfman
Neil M
NM
Department of Inflammation, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. nwolfman@wyeth.com
McPherron
Alexandra C
AC
Pappano
William N
WN
Davies
Monique V
MV
Song
Kening
K
Tomkinson
Kathleen N
KN
Wright
Jill F
JF
Zhao
Liz
L
Sebald
Suzanne M
SM
Greenspan
Daniel S
DS
Lee
Se-Jin
SJ
D000818:Animals; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000254:growth & development*; D055435:Myostatin; D011498:Protein Precursors / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055394:Tolloid-Like Metalloproteinases; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; C525911:MSTN protein, human; C525912:Mstn protein, mouse; D055435:Myostatin; D011498:Protein Precursors; D011506:Proteins; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D008156:Luciferases; D045726:Metalloproteases; D055394:Tolloid-Like Metalloproteinases; D008666:Metalloendopeptidases; C525705:BMP1 protein, human; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1