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

Area of Science:

• Biochemistry
• Muscle Biology
• Therapeutics

Background:

• Follistatin (FST) is a glycoprotein that supports skeletal muscle growth and repair by inhibiting TGF-β superfamily ligands.
• FST has potential therapeutic applications for neuromuscular diseases.

Purpose of the Study:

• To evaluate a novel follistatin fusion protein (FST288-Fc) for localized skeletal muscle growth.
• To leverage the heparin-binding capacity of the FST-288 isoform for targeted delivery.

Main Methods:

• Surface plasmon resonance and cell-based assays to assess FST288-Fc binding and neutralization of activins and myostatin.
• Intramuscular and systemic administration of FST288-Fc and ActRIIB-Fc in mice.
• Analysis of muscle growth, body composition (NMR), and systemic effects.

Main Results:

• FST288-Fc effectively binds and neutralizes activin A, activin B, myostatin (GDF8), and GDF11 in vitro.
• Intramuscular FST288-Fc induced dose-dependent, localized muscle growth without affecting surrounding muscles.
• Systemic FST288-Fc showed no impact on overall muscle mass or body composition, unlike ActRIIB-Fc.
• Rapid proteolysis of circulating FST288-Fc restricted its activity to the administration site.

Conclusions:

• FST288-Fc enables targeted, localized skeletal muscle growth via intramuscular injection.
• This approach minimizes systemic adverse effects, differentiating it from systemic treatments.
• FST288-Fc is a promising agent for treating focal, asymmetric, or heterogeneous muscle atrophy disorders.