Nishizawa Hitoshi, Matsuda Morihiro, Yamada Yukio, Kawai Kenichiro, Suzuki Emi, Makishima Makoto, Kitamura Toshio, Shimomura Iichiro
Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871.
J Biol Chem. 2004 May 7;279(19):19391-5. doi: 10.1074/jbc.C400066200. Epub 2004 Mar 24.
Skeletal muscle is involved in the homeostasis of glucose and lipid metabolism. We hypothesized that the skeletal muscle produces and secretes bioactive factor(s), similar to adipocytokines secreted by fat tissue. Here, we report the identification of a novel secretory factor, musclin, by signal sequence trap of mouse skeletal muscle cDNAs. Musclin cDNA encoded 130 amino acids, including NH(2)-terminal 30-amino acid signal sequence. Musclin protein contained a region homologous to natriuretic peptide family, and KKKR, a putative serine protease cleavage site, similar to the natriuretic peptide family. Full-length musclin protein and KKKR-dependent cleaved form were secreted in media of musclin cDNA-transfected mammalian cell cultures. Musclin mRNA was expressed almost exclusively in the skeletal muscle of mice. Musclin mRNA levels in skeletal muscle were markedly low in fasted, increased upon re-feeding, and were low in streptozotocin-treated insulin-deficient mice. Musclin mRNA expression was induced at late stage in the differentiation of C2C12 myocytes. In myocytes, insulin increased, while epinephrine, isoproterenol, and forskolin reduced musclin mRNA, all of which are known to increase the cellular content of cyclic AMP, a counter-regulator to insulin. Pathologically, overexpression of musclin mRNA was noted in the muscles of obese insulin-resistant KKAy mice. Functionally, recombinant musclin significantly attenuated insulin-stimulated glucose uptake and glycogen synthesis in myocytes. In conclusion, we identified musclin, a novel skeletal muscle-derived secretory factor. Musclin expression level is tightly regulated by nutritional changes and its physiological role could be linked to glucose metabolism.
骨骼肌参与葡萄糖和脂质代谢的稳态。我们推测骨骼肌会产生并分泌生物活性因子，类似于脂肪组织分泌的脂肪细胞因子。在此，我们报告通过小鼠骨骼肌cDNA的信号序列捕获鉴定出一种新型分泌因子——肌肉素。肌肉素cDNA编码130个氨基酸，包括氨基端30个氨基酸的信号序列。肌肉素蛋白包含一个与利钠肽家族同源的区域，以及一个类似于利钠肽家族的假定丝氨酸蛋白酶切割位点KKKR。全长肌肉素蛋白和依赖KKKR切割的形式在转染了肌肉素cDNA的哺乳动物细胞培养物的培养基中分泌。肌肉素mRNA几乎只在小鼠的骨骼肌中表达。禁食时骨骼肌中的肌肉素mRNA水平显著降低，重新进食后升高，在链脲佐菌素处理的胰岛素缺乏小鼠中则较低。肌肉素mRNA表达在C2C12肌细胞分化的后期被诱导。在肌细胞中，胰岛素会增加肌肉素mRNA水平，而肾上腺素、异丙肾上腺素和福斯高林会降低其水平，所有这些都已知会增加细胞内环磷酸腺苷（一种胰岛素的反调节因子）的含量。在病理方面，肥胖胰岛素抵抗的KKAy小鼠的肌肉中观察到肌肉素mRNA的过表达。在功能方面，重组肌肉素显著减弱了胰岛素刺激的肌细胞葡萄糖摄取和糖原合成。总之，我们鉴定出了肌肉素，一种新型的骨骼肌来源的分泌因子。肌肉素的表达水平受到营养变化的严格调控，其生理作用可能与葡萄糖代谢有关。
