PT  - JOURNAL ARTICLE
AU  - Roselyne Castonguay
AU  - Jennifer Lachey
AU  - Samantha Wallner
AU  - Jamie Strand
AU  - Katia Liharska
AU  - Abigail E. Watanabe
AU  - Marishka Cannell
AU  - Monique V. Davies
AU  - Dianne Sako
AU  - Megan E. Troy
AU  - Lavanya Krishnan
AU  - Aaron W. Mulivor
AU  - Huiming Li
AU  - Sarah Keates
AU  - Mark J. Alexander
AU  - R. Scott Pearsall
AU  - Ravi Kumar
TI  - Follistatin-288-Fc Fusion Protein Promotes Localized Growth of Skeletal Muscle
AID  - 10.1124/jpet.118.252304
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.252304
4099  - http://jpet.aspetjournals.org/content/early/2018/12/18/jpet.118.252304.short
4100  - http://jpet.aspetjournals.org/content/early/2018/12/18/jpet.118.252304.full
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.