RT Journal Article
SR Electronic
T1 Follistatin-288-Fc Fusion Protein Promotes Localized Growth of Skeletal Muscle
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.118.252304
DO 10.1124/jpet.118.252304
A1 Roselyne Castonguay
A1 Jennifer Lachey
A1 Samantha Wallner
A1 Jamie Strand
A1 Katia Liharska
A1 Abigail E. Watanabe
A1 Marishka Cannell
A1 Monique V. Davies
A1 Dianne Sako
A1 Megan E. Troy
A1 Lavanya Krishnan
A1 Aaron W. Mulivor
A1 Huiming Li
A1 Sarah Keates
A1 Mark J. Alexander
A1 R. Scott Pearsall
A1 Ravi Kumar
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/12/18/jpet.118.252304.abstract
AB Follistatin is an endogenous glycoprotein that promotes growth and repair of skeletal muscle by sequestering inhibitory ligands of the transforming growth factor-β (TGF-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 (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 nuclear magnetic resonance, 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.