title: Follistatin: a novel therapeutic for the improvement of muscle regeneration.
abstract: Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. The objective of this study was to explore the use of an engineered follistatin therapeutic created by fusing FST315 lacking heparin binding activity to the N terminus of a murine IgG1 Fc (FST315-ΔHBS-Fc) as a systemic therapeutic agent in models of muscle injury. Systemic administration of this molecule was found to increase body weight and lean muscle mass after weekly administration in normal mice. Subsequently, we tested this agent in several models of muscle injury, which were chosen based on their severity of damage and their ability to reflect clinical settings. FST315-ΔHBS-Fc treatment proved to be a potent inducer of muscle remodeling and regeneration. FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. Collectively, these data demonstrate the benefits of a therapeutically viable form of FST that can be leveraged as an alternate means of ameliorating muscle regeneration.
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University, Indianapolis, Indiana (B.C.Y., J.M.W., G.D.); and Musculoskeletal Research (B.C.Y., Y.W., P.S., A.M., H.U.B., J.A., V.K.), Departments of Drug Disposition Development/Commercialization, and Biotechnology Discovery Research (J.E.C., A.D.-M.), and Translational Sciences-Molecular Pathology, Lilly Research Laboratories, Indianapolis, Indiana (J.M.W.).
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Yaden
authors.forename: Johnny E
authors.initials: JE
authors.lastname: Croy
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Amita
authors.initials: A
authors.lastname: Datta-Mannan
authors.forename: Pamela
authors.initials: P
authors.lastname: Shetler
authors.forename: Andrea
authors.initials: A
authors.lastname: Milner
authors.forename: Henry U
authors.initials: HU
authors.lastname: Bryant
authors.forename: Jessica
authors.initials: J
authors.lastname: Andrews
authors.forename: Guoli
authors.initials: G
authors.lastname: Dai
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
mesh_terms: D000818:Animals; D038681:Follistatin / Q000235:genetics / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics*; D007074:Immunoglobulin G / Q000235:genetics*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D012038:Regeneration
chemical_list: D038681:Follistatin; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins