Abstract
Follistatin is an endogenous glycoprotein that promotes growth and repair of skeletal muscle by sequestering inhibitory ligands of the transforming growth factor-β superfamily and may therefore have therapeutic potential for neuromuscular diseases. Here, we sought to determine the suitability of a newly engineered follistatin fusion protein (FST288-Fc) to promote localized, rather than systemic, growth of skeletal muscle by capitalizing on the intrinsic heparin-binding ability of the follistatin-288 isoform. As determined by surface plasmon resonance and cell-based assays, FST288-Fc binds to activin A, activin B, myostatin (growth differentiation factor GDF8), and GDF11 with high affinity and neutralizes their activity in vitro. Intramuscular administration of FST288-Fc in mice induced robust, dose-dependent growth of the targeted muscle but not of surrounding or contralateral muscles, in contrast to the systemic effects of a locally administered fusion protein incorporating activin receptor type IIB (ActRIIB-Fc). Furthermore, systemic administration of FST288-Fc in mice did not alter muscle mass or body composition as determined by NMR, which again contrasts with the pronounced systemic activity of ActRIIB-Fc when administered by the same route. Subsequent analysis revealed that FST288-Fc in the circulation undergoes rapid proteolysis, thereby restricting its activity to individual muscles targeted by intramuscular administration. These results indicate that FST288-Fc can produce localized growth of skeletal muscle in a targeted manner with reduced potential for undesirable systemic effects. Thus, FST288-Fc and similar agents may be beneficial in the treatment of disorders with muscle atrophy that is focal, asymmetric, or otherwise heterogeneous.
Highlights
Disease-dependent myopathies can produce focal weakness in skeletal muscle, including deficits that are asymmetric or differentially impact individual muscles or muscle groups (Terry et al, 2018)
We generated a dimeric Fc fusion protein based on the native follistatin-288 isoform (FST288) isoform by fusing human FST288 to a human IgG1 Fc domain (Fig. 1B)
We evaluated whether FST288-Fc interacts with the vascular regulatory ligand BMP9 (David et al, 2008) but did not observe appreciable binding
Summary
Disease-dependent myopathies can produce focal weakness in skeletal muscle, including deficits that are asymmetric or differentially impact individual muscles or muscle groups (Terry et al, 2018). Among disorders with such deficits are many rare and debilitating neuromuscular diseases with no known cure and limited treatment options. GDF11, which is closely related to myostatin (Walker et al, 2017), has been implicated as an inhibitor of muscle growth (Egerman et al, 2015; Hammers et al, 2017; Zimmers et al, 2017) These ligands exert their effects by triggering formation of heteromeric complexes between certain type I and type II receptors that activate the small mothers against decapentaplegic 2/3 (Smad2/3) pathway to regulate gene transcription (Schmierer and Hill, 2007)
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