title: Inhibition of activin A ameliorates skeletal muscle injury and rescues contractile properties by inducing efficient remodeling in female mice.
abstract: Activin A, a member of the transforming growth factor-β superfamily, provides pleiotropic regulation of fibrosis and inflammation. We aimed at determining whether selective inhibition of activin A would provide a regenerative benefit. The introduction of activin A into normal muscle increased the expression of inflammatory and muscle atrophy genes Tnf, Tnfrsf12a, Trim63, and Fbxo32 by 3.5-, 10-, 2-, and 4-fold, respectively. The data indicate a sensitive response of muscle to activin A. Two hours after cardiotoxin-induced muscle damage, local activin A protein expression increased by threefold to ninefold. Neutralization of activin A with a specific monoclonal antibody in this muscle injury model decreased the muscle protein levels of lymphotoxin α and Il17a by 32% and 42%, respectively. Muscle histopathological features showed that activin A antibody-treated mice displayed an increase in muscle degradation, with the concomitant 9.2-fold elevation in F4/80-positive cells 3 days after injury. At the same time, the number of Pax7/Myod1-positive cells also increased, indicative of potentiated muscle precursor activation. Ultimately, activin A inhibition resulted in rapid recovery of muscle contractile properties indicated by a restoration of maximum and specific force. In summary, selective inhibition of activin A with a monoclonal antibody in muscle injury leads to the early onset of tissue degradation and subsequent enhanced myogenesis, thereby accelerating muscle repair and functional recovery.
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana; Department of Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Yaden
authors.affiliation: Department of Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Yan X
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana; Division of Translational Sciences-Molecular Pathology, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Department of Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Culver
authors.affiliation: Department of Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Andrea
authors.initials: A
authors.lastname: Milner
authors.affiliation: Departments of Drug Disposition Development/Commercialization and Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Amita
authors.initials: A
authors.lastname: Datta-Mannan
authors.affiliation: Department of Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Pamela
authors.initials: P
authors.lastname: Shetler
authors.affiliation: Departments of Drug Disposition Development/Commercialization and Biotechnology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana.
authors.forename: Johnny E
authors.initials: JE
authors.lastname: Croy
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana. Electronic address: gdai@iupui.edu.
authors.forename: Guoli
authors.initials: G
authors.lastname: Dai
authors.affiliation: Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana; Department of Musculoskeletal Research, Lilly Research Laboratories, Indianapolis, Indiana. Electronic address: krishnan_gary@lilly.com.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors*; D000818:Animals; D018274:Electroporation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000293:injuries* / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D059467:Transcriptome
chemical_list: C422405:activin A; D028341:Activins