Abstract
Growth differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related TGFβ family members that are often believed to serve similar functions due to their high homology. However, genetic studies in animals provide clear evidence that they perform distinct roles. While the loss of Mstn leads to hypermuscularity, the deletion of Gdf11 results in abnormal skeletal patterning and organ development. The perinatal lethality of Gdf11-null mice, which contrasts with the long-term viability of Mstn-null mice, has led most research to focus on utilizing recombinant GDF11 proteins to investigate the postnatal functions of GDF11. However, the reported outcomes of the exogenous application of recombinant GDF11 proteins are controversial partly because of the different sources and qualities of recombinant GDF11 used and because recombinant GDF11 and MSTN proteins are nearly indistinguishable due to their similar structural and biochemical properties. Here, we analyze the similarities and differences between GDF11 and MSTN from an evolutionary point of view and summarize the current understanding of the biological processing, signaling, and physiological functions of GDF11 and MSTN. Finally, we discuss the potential use of recombinant GDF11 as a therapeutic option for a wide range of medical conditions and the possible adverse effects of GDF11 inhibition mediated by MSTN inhibitors.
Highlights
Cytokines of the transforming growth factor β (TGFβ) family, including activins, growth differentiation factors (GDFs), bone morphogenetic proteins (BMPs), and TGFβs, have been extensively implicated in the regulation of developmental patterning, cellular proliferation and differentiation, and the maintenance of tissue homeostasis[1]
Our findings revealed that both time-specific ubiquitous deletion and limb mesenchyme-specific deletion of Gdf[11] resulted in diminished bone mass in young adult mice, suggesting that Growth differentiation factor 11 (GDF11) endogenously promotes bone development, in contrast to MSTN26
Conclusion and future perspectives The remarkable sequence similarity between GDF11 and MSTN led to the assumption that the two molecules are functionally redundant
Summary
Suh and Lee Experimental & Molecular Medicine (2020) 52:1673–1693 first present the similarities and differences between GDF11 and MSTN from an evolutionary point of view and summarize the insights obtained to date regarding the biological processing, signaling mechanisms, and physiological functions of GDF11 and MSTN during development, adulthood, and aging. Many of the reported functions of the invertebrate MSTN/GDF11 protein are very different from the well-established suppressive role of vertebrate MSTN in the development of multiple tissues, and the broad expression pattern of the ancestral protein more closely resembles the expression pattern of vertebrate GDF11 11,13,15–19. MSTN share 89% amino acid sequence identity in their mature domains, which differ by only 11 residues (Fig. 2b, c), their prodomains share only 48% amino acid sequence identity This suggests the strong possibility that GDF11 prodomains may be associated with distinct and crucial extracellular regulatory mechanisms and biological functions that are not observed for the prodomains of MSTN, which warrants further investigation that may uncover significant differences that were previously unnoticed for the mature ligands
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