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

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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. Significance The TGF-β family encompasses a large number of secreted proteins that regulate embryonic development and adult tissue homeostasis. Growth and differentiation factor (GDF) -associated serum protein-1 (GASP-1) and GASP-2 are related proteins capable of binding and inhibiting two family members, myostatin and GDF-11. Here, we show that mice genetically engineered to lack GASP-1 and/or GASP-2 exhibit muscle and skeletal phenotypes consistent with overactivity of myostatin and/or GDF-11. These studies also reveal the enormous complexity of this regulatory system in vivo and the delicate balance that must be maintained between signaling molecules and their inhibitory proteins for proper levels of signaling to be achieved.

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