GDF11 and aging biology - controversies resolved and pending

Abstract

Since the exogenous administration of GDF11, a TGF-ß superfamily member, was reported to have beneficial effects in some models of human disease, there have been many research studies in GDF11 biology. However, many studies have now confirmed that exogenous administration of GDF11 can improve physiology in disease models, including cardiac fibrosis, experimental stroke, and disordered metabolism. GDF11 is similar to GDF8 (also called Myostatin), differing only by 11 amino acids in their mature signaling domains. These two proteins are now known to be biochemically different both in vitro and in vivo. GDF11 is much more potent than GDF8 and induces more strongly SMAD2 phosphorylation in the myocardium compared to GDF8. GDF8 and GDF11 prodomain are only 52% identical and are cleaved by different Tolloid proteases to liberate the mature signaling domain from inhibition of the prodomain. Here, we review the state of GDF11 biology, highlighting both resolved and remaining controversies.

Keywords: GDF11; aging; brain; heart; skeletal muscle; systemic factor.

Figure 1.

Distinct structure and expression patterns of GDF8 and GDF11. GDF8 and GDF11 share 89% amino acid identity in their mature domain, but only 52% in their prodomain. During processing, the signal sequence (SS) is removed, and the pre-pro-ligands are cleaved by Furin and Tolloid proteases (TLDs) to prepare the mature ligand for future signaling. GDF8, expressed predominantly in skeletal muscle, is cleaved by all TLDs and preferentially by TLL2 due to the availability of this TLD in the muscle, while the ubiquitously expressed GDF11 is cleaved preferentially by BMP1 and TLL1^[6]. Figure made by @Biorender.

Figure 2.

Proteolytic processing of GDF8 and GDF11 prodomains is a critical regulatory step. Proteolytic processing is necessary to pass from an unprocessed pre-pro complex protein to an active ligand able to signal. After a signal peptidase, the Furin protein recognizes and cleaves a specific motif -RXXR- between the prodomain and the mature domain. The inactive latent complex is then cleaved by the Tolloids family of protease to separate the prodomain from the active ligand. After cleavage, the prodomain is readily displaced when the mature ligand binds to the type II receptor and is likely degraded. Upon binding the type II receptor, a type I receptor is recruited and phosphorylated to activate downstream signaling pathways. The mature domain can also interact with inhibitors such as WFIKKN1, WFIKKN2, Follistatin (FS), or FSTL3.

Figure 3.

Different potential states of GDF11. (i) Latent, with green and purple dimer and brown prodomains; (ii) Triggered as realized through acid activation; (iii) Tolloid processed; (iv) free ligand; and (v) antagonist bound with red and pink antagonists. + denotes active signaling states. Arrows indicate the possibility that some specific forms may change with age.

Figure 4.

Human genetic diseases associated with GDF11 mutations. (A) 7 mutation sites have been identified in the GDF11 gene associated with several defects such as cleft palate and skeletal abnormalities. Mutations 1 and 2 are located in the prodomain, Mutations 3 and 4 in the Furin cleavage site, and Mutations 5–7 in the mature domain of GDF11. (B) Summary table of GDF11 mutations identified in humans. (+) indicates defects; (−) indicates no defect. + Ribs suggest skeleton defects. (C) Schematic depicting the functional impact of mutation 3, located in the Furin cleavage site, highlighting the importance of Furin cleavage for GDF11 activity.