Identification of a novel pool of extracellular pro-myostatin in skeletal muscle.
Myostatin, a transforming growth factor-beta superfamily ligand, negatively regulates skeletal muscle growth. Generation of the mature signaling peptide requires cleavage of pro-myostatin by a proprotein convertase, which is thought to occur constitutively in the Golgi apparatus. In serum, mature myostatin is found in an inactive, non-covalent complex with its prodomain. We find that in skeletal muscle, unlike serum, myostatin is present extracellularly as uncleaved pro-myostatin. In cultured cells, co-expression of pro-myostatin and latent transforming growth factor-beta-binding protein-3 (LTBP-3) sequesters pro-myostatin in the extracellular matrix, and secreted pro-myostatin can be cleaved extracellularly by the proprotein convertase furin. Co-expression of LTBP-3 with myostatin reduces phosphorylation of Smad2, and ectopic expression of LTBP-3 in mature mouse skeletal muscle increases fiber area, consistent with reduction of myostatin activity. We propose that extracellular pro-myostatin constitutes the major pool of latent myostatin in muscle. Post-secretion activation of this pool by furin family proprotein convertases may therefore represent a major control point for activation of myostatin in skeletal muscle.
Anderson
Sarah B
SB
Department of Developmental Biology, Harvard School of Dental Medicine, Massachusetts 02115, USA.
Goldberg
Alfred L
AL
Whitman
Malcolm
M
D000818:Animals; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism*; D055435:Myostatin; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D014981:Xenopus
C509038:LTBP3 protein, human; D053779:Latent TGF-beta Binding Proteins; D008024:Ligands; C509039:Ltbp3 protein, mouse; C525911:MSTN protein, human; C525912:Mstn protein, mouse; D055435:Myostatin; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta