Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 39; pp. E3713 - E3722
• Main Authors: Lee, Yun-Sil, Lee, Se-Jin
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.09.2013; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Body Patterning - genetics; Bone and Bones - embryology; Bone and Bones - metabolism; Bone Morphogenetic Proteins - antagonists & inhibitors; Bone Morphogenetic Proteins - deficiency; Bone Morphogenetic Proteins - metabolism; Cardiotoxins; Carrier Proteins - genetics; Carrier Proteins - metabolism; Follistatin - deficiency; Follistatin - metabolism; Gene Expression Profiling; Gene Expression Regulation; Genetics; Genotype & phenotype; Growth Differentiation Factors - antagonists & inhibitors; Growth Differentiation Factors - deficiency; Growth Differentiation Factors - metabolism; Ligands; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Mutation - genetics; Myostatin - antagonists & inhibitors; Myostatin - genetics; Myostatin - metabolism; Organ Size; Oxidation-Reduction; PNAS Plus; Protein Binding; Protein-Serine-Threonine Kinases - metabolism; Proteins; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Transforming Growth Factor beta - metabolism; Regeneration - genetics; Rodents; Signal Transduction - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1309907110

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.