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Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease

Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the transforming growth factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the pote...

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Autores principales: Pearsall, R. S., Davies, M. V., Cannell, M., Li, J., Widrick, J., Mulivor, A. W., Wallner, S., Troy, M. E., Spaits, M., Liharska, K., Sako, D., Castonguay, R., Keates, S., Grinberg, A. V., Suragani, R. N. V. S., Kumar, R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684588/
https://www.ncbi.nlm.nih.gov/pubmed/31388039
http://dx.doi.org/10.1038/s41598-019-47818-w
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author Pearsall, R. S.
Davies, M. V.
Cannell, M.
Li, J.
Widrick, J.
Mulivor, A. W.
Wallner, S.
Troy, M. E.
Spaits, M.
Liharska, K.
Sako, D.
Castonguay, R.
Keates, S.
Grinberg, A. V.
Suragani, R. N. V. S.
Kumar, R.
author_facet Pearsall, R. S.
Davies, M. V.
Cannell, M.
Li, J.
Widrick, J.
Mulivor, A. W.
Wallner, S.
Troy, M. E.
Spaits, M.
Liharska, K.
Sako, D.
Castonguay, R.
Keates, S.
Grinberg, A. V.
Suragani, R. N. V. S.
Kumar, R.
author_sort Pearsall, R. S.
collection PubMed
description Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the transforming growth factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the potential of ACE-083 – a locally acting, follistatin-based fusion protein – as a novel therapeutic agent for focal or asymmetric myopathies. Characterization of ACE-083 in vitro revealed its high affinity for heparin and extracellular matrix while surface plasmon resonance and cell-based assays confirmed that ACE-083 binds and potently neutralizes myostatin, activin A, activin B and growth differentiation factor 11 (GDF11). Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, with no evidence of systemic muscle effects or endocrine perturbation. Importantly, ACE-083 also increased the force of isometric contraction in situ by the injected tibialis anterior muscle in wild-type mice and disease models and increased ankle dorsiflexion torque in CMT mice. Our results demonstrate the potential of ACE-083 as a therapeutic agent for patients with CMT, muscular dystrophy and other disorders with focal or asymmetric muscle atrophy or weakness.
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spelling pubmed-66845882019-08-11 Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease Pearsall, R. S. Davies, M. V. Cannell, M. Li, J. Widrick, J. Mulivor, A. W. Wallner, S. Troy, M. E. Spaits, M. Liharska, K. Sako, D. Castonguay, R. Keates, S. Grinberg, A. V. Suragani, R. N. V. S. Kumar, R. Sci Rep Article Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the transforming growth factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the potential of ACE-083 – a locally acting, follistatin-based fusion protein – as a novel therapeutic agent for focal or asymmetric myopathies. Characterization of ACE-083 in vitro revealed its high affinity for heparin and extracellular matrix while surface plasmon resonance and cell-based assays confirmed that ACE-083 binds and potently neutralizes myostatin, activin A, activin B and growth differentiation factor 11 (GDF11). Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, with no evidence of systemic muscle effects or endocrine perturbation. Importantly, ACE-083 also increased the force of isometric contraction in situ by the injected tibialis anterior muscle in wild-type mice and disease models and increased ankle dorsiflexion torque in CMT mice. Our results demonstrate the potential of ACE-083 as a therapeutic agent for patients with CMT, muscular dystrophy and other disorders with focal or asymmetric muscle atrophy or weakness. Nature Publishing Group UK 2019-08-06 /pmc/articles/PMC6684588/ /pubmed/31388039 http://dx.doi.org/10.1038/s41598-019-47818-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pearsall, R. S.
Davies, M. V.
Cannell, M.
Li, J.
Widrick, J.
Mulivor, A. W.
Wallner, S.
Troy, M. E.
Spaits, M.
Liharska, K.
Sako, D.
Castonguay, R.
Keates, S.
Grinberg, A. V.
Suragani, R. N. V. S.
Kumar, R.
Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
title Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
title_full Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
title_fullStr Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
title_full_unstemmed Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
title_short Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
title_sort follistatin-based ligand trap ace-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684588/
https://www.ncbi.nlm.nih.gov/pubmed/31388039
http://dx.doi.org/10.1038/s41598-019-47818-w
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