Systemic administration of monovalent follistatin-like 3-Fc-fusion protein increases muscle mass in mice
Takayuki Ozawa,
Masato Morikawa,
Yasuyuki Morishita,
Kazuki Ogikubo,
Fumiko Itoh,
Daizo Koinuma,
Per-Åke Nygren,
Kohei Miyazono
Affiliations
Takayuki Ozawa
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Masato Morikawa
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
Yasuyuki Morishita
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Kazuki Ogikubo
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Fumiko Itoh
Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
Daizo Koinuma
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Per-Åke Nygren
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, AlbaNova University Center, Royal Institute of Technology, 106 91 Stockholm, Sweden; Science for Life Laboratory, 171 65 Solna, Sweden
Kohei Miyazono
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Corresponding author
Summary: Targeting 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 mass in vivo. Our results indicate that the monovalent FSTL3-based therapy overcomes the difficulties of current anti-GDF8 therapies.
