title: Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2.
abstract: Myostatin (MSTN) and growth and differentiation factor-11 (GDF-11) are highly related TGF-β family members that have distinct biological functions. MSTN is expressed primarily in skeletal muscle and acts to limit muscle growth. GDF-11 is expressed more widely and plays multiple roles, including regulating axial skeletal patterning during development. Several MSTN and GDF-11 binding proteins have been identified, including GDF-associated serum protein-1 (GASP-1) and GASP-2, which are capable of inhibiting the activities of these ligands. Here, we show that GASP-1 and GASP-2 act by blocking the initial signaling event (namely, the binding of the ligand to the type II receptor). Moreover, we show that mice lacking Gasp1 and Gasp2 have phenotypes consistent with overactivity of MSTN and GDF-11. Specifically, we show that Gasp2(-/-) mice have posteriorly directed transformations of the axial skeleton, which contrast with the anteriorly directed transformations seen in Gdf11(-/-) mice. We also show that both Gasp1(-/-) and Gasp2(-/-) mice have reductions in muscle weights, a shift in fiber type from fast glycolytic type IIb fibers to fast oxidative type IIa fibers, and impaired muscle regeneration ability, which are the reverse of what are seen in Mstn(-/-) mice. All of these findings suggest that both GASP-1 and GASP-2 are important modulators of GDF-11 and MSTN activity in vivo.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism; D054715:Cardiotoxins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D038681:Follistatin / Q000172:deficiency / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055412:Growth Differentiation Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D010084:Oxidation-Reduction; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins; D054715:Cardiotoxins; D002352:Carrier Proteins; D038681:Follistatin; C119153:Gdf11 protein, mouse; C479636:Gprasp1 protein, mouse; C485065:Gprasp2 protein, mouse; D055412:Growth Differentiation Factors; D047908:Intracellular Signaling Peptides and Proteins; D055435:Myostatin; D043562:Receptors, G-Protein-Coupled; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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