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Foxo1 represses expression of musclin, a skeletal muscle-derived secretory factor |
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| Authors: | Yasui Atsutaka Nishizawa Hitoshi Okuno Yosuke Morita Kentaro Kobayashi Hironori Kawai Kenichiro Matsuda Morihiro Kishida Ken Kihara Shinji Kamei Yasutomi Ogawa Yoshihiro Funahashi Tohru Shimomura Iichiro |
| Affiliation: | a Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan b Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Osaka University, Osaka, Japan c Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan d Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan |
| Abstract: | Musclin is a novel skeletal muscle-derived secretory factor, whose mRNA level is markedly regulated by nutritional status. In the present study, we investigated the mechanism of musclin mRNA regulation by insulin. In C2C12 myocytes, insulin-induced upregulation of musclin mRNA was significantly decreased by treatment of phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and was abolished in C2C12 myocytes stably expressing a constitutively active Foxo1 (Foxo1-3A), suggesting the involvement of Foxo1 in the regulation of musclin mRNA. Promoter deletion analysis of musclin promoter revealed that the region of −303/−123 is important for the repression of promoter activity by Foxo1. Chromatin immunoprecipitation assay showed that Foxo1 bound to musclin promoter. Musclin mRNA level was markedly downregulated in gastrocnemius muscle of Foxo1 transgenic mice. Our results demonstrated that Foxo1 downregulates musclin mRNA expression both in vitro and in vivo, which should explain insulin-mediated upregulation of this gene in muscle cells. |
| Keywords: | Musclin Foxo1 Myokine Skeletal muscle |
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