Follistatin-288-Fc Fusion Protein Promotes Localized Growth of Skeletal Muscle.

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.

• Authors: Roselyne Castonguay, Jennifer Lachey, Samantha Wallner, Jamie Strand, Katia Liharska, Abigail E Watanabe, Marishka Cannell, Monique V Davies, Dianne Sako, Megan E Troy, Lavanya Krishnan, Aaron W Mulivor, Huiming Li, Sarah Keates, Mark J Alexander, R Scott Pearsall, Ravi Kumar
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 368 Issue 3 Pg. 435-445 (03 2019) ISSN: 1521-0103 [Electronic] United States
• PMID: 30563942 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Author(s).

Chemical References

• Follistatin
• Immunoglobulin G
• Recombinant Fusion Proteins
• follistatin, 288-amino acid isoform

Topics

• Amino Acid Sequence
• Animals
• Dose-Response Relationship, Drug
• Follistatin (administration & dosage, genetics, metabolism)
• Humans
• Immunoglobulin G (administration & dosage, genetics, metabolism)
• Injections, Intramuscular
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Skeletal (drug effects, growth & development, metabolism)
• Protein Structure, Secondary
• Recombinant Fusion Proteins (administration & dosage, genetics, metabolism)