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标题：Systemic administration of monovalent follistatin-like 3-Fc-fusion protein increases muscle mass in mice
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作者：Takayuki Ozawa ; Masato Morikawa ; Yasuyuki Morishita 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：5
页码：1-24
DOI：10.1016/j.isci.2021.102488
语种：English
出版社：Elsevier
摘要：SummaryTargeting the signaling pathway of growth differentiation factor 8 (GDF8), also known as myostatin, has been regarded as a promising strategy to increase muscle mass in the elderly and in patients. Accumulating evidence in animal models and clinical trials has indicated that a rational approach is to inhibit a limited number of transforming growth factor β (TGF-β) family ligands, including GDF8 and activin A, without affecting other members. Here, we focused on one of the endogenous antagonists against TGF-β family ligands, follistatin-like 3 (FSTL3), which mainly binds and neutralizes activins, GDF8, and GDF11. Although bivalent human FSTL3 Fc-fusion protein was rapidly cleared from mouse circulation similar to follistatin (FST)-Fc, monovalent FSTL3-Fc (mono-FSTL3-Fc) generated with the knobs-into-holes technology exhibited longer serum half-life. Systemic administration of mono-FSTL3-Fc in mice induced muscle fiber hypertrophy and increased muscle massin vivo. Our results indicate that the monovalent FSTL3-based therapy overcomes the difficulties of current anti-GDF8 therapies.Graphical abstractDisplay OmittedHighlights•FSTL3-Fc has a more specific binding profile for TGF-β family ligands than ActRIIB-Fc.•Bivalent two-armed FSTL3-Fc is rapidly cleared from mouse circulation.•Monovalent FSTL3-Fc has longer serum half-life and causes systemic muscle hypertrophy.•ActRIIB-Fc-related side effects are not detected in monovalent FSTL3-Fc-treated mice.Musculoskeletal medicine; Physiology; Human metabolism