Myostatin对成肌细胞糖代谢的影响
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摘要
肌肉抑制素Myostatin(MSTN)是由骨骼肌分泌抑制骨骼肌生长发育的生长因子,它对于骨骼肌的自我稳态调节具有重要的作用。由于MSTN可以随血液到达全身,故靶器官可能并不限于骨骼肌。已有研究提示它可能参与机体蛋白质、糖类和脂肪等物质代谢的调节,如脂肪组织就是已被证实的除骨骼肌以外受MSTN调节的组织。本课题首次从细胞水平上研究了MSTN对成肌细胞糖代谢的影响。
葡萄糖消耗试验显示,MSTN可以促进分化的C2C12肌管消耗培养基中的葡萄糖,这种促进细胞吸收葡萄糖的作用与Insulin相似,二者联用时还呈现协同作用。MSTN对糖消耗的促进作用不依赖于血清中的其它激素或因子,而且不是由于MSTN本身的细胞毒性所致。与已分化的肌管不同,MSTN不促进未分化的成肌细胞消耗葡萄糖,这也与Insulin的作用类似。因此,MSTN的降糖效应可能与特异性表达于分化后骨骼肌的GLUT4相关。有趣的是,在进化上完全缺失GLUT4的鸡原代肌管中,Insulin对其糖消耗的促进作用确实明显减弱,但MSTN仍然有明显的促进作用,提示MSTN促进糖消耗作用可能还有其它葡萄糖转运载体参与。
然而在葡萄糖摄取实验中,MSTN短时间内直接抑制糖摄取;但若仅以MSTN预处理1小时则仍可促进糖摄取。这些结果提示MSTN对葡萄糖转运作用的复杂性,因为糖摄取观察瞬时的葡萄糖转运作用,这一过程由骨骼肌中Insulin敏感的GLUT4载体介导,而糖消耗实验时间较长,可能还有其它非Insulin敏感的糖转运载体参与。
综上,本研究揭示了MSTN在控制骨骼肌的增殖、分化之外,还会影响其葡萄糖代谢过程,全面阐明MSTN对骨骼肌糖代谢的调控机制,将为全新认识和界定骨骼肌在胰岛素抵抗和/或2型糖尿病的发生、发展过程中的作用奠定基础,也为将来的糖尿病治疗提供了可能的药物靶点。
Myostatin (MSTN) is a growth factor, which is secreted by skeletal muscle and inhibits the growth and proliferation of skeletal muscle itself. It has a crucial role on the regulation of skeletal muscle homeostasis. Since MSTN can be distributed to the whole body by circulation, its function may not only be limited in skeletal muscle. It has been identified that the adipo-tissue could be regulated by MSTN. The increased expression of Myostatin gene during some diseases progression will cause the degradation of structure proteins in skeletal muscle, and followed by cachexia. Thus, MSTN shouldn't be only consided as a regulator of skeletal muscle mass, but also an endocrine factor, which may participate the regulation of metabolism of lipid and proteins etc.
Our project mainly focused on the affect of MSTN on glucose metabolism in celll culture system. The results of glucose consumption assay show that MSTN could promote the glucose consumption in differentiated C2C2 myotubes. Those promotion effects were similar to Insulin, and the combination of those two drugs could synergize with each other. The function of MSTN on glucose consumption didn't depend on other hormones or factors in the serum, nor relate to the cyto-toxicity of MSTN. Since MSTN couldn't promote the glucose metabolism in undifferentiated myoblasts, its function may rely on the GLUT4, which only appears in differentiated myotubes. The RT-PCR results suggested that MSTN couldn't upregulate the GLUT4 transcription, which indicate that MSTN may have effect on the translocation of GLUT4 from cytosol to cell membrane.
Interestingly, in the GLUT4 deficient chicken myotubes, the promotion effects of Insulin on glucose consumption were not that apparent like in mice, while MSTN's effects were still obviously. Those results indicated that other types of glucose transporter might involve in MSTN's promotion effects on glucose metabolism.
However, the glucose uptake experiments were contradictorily. MSTN could inhibit the glucose uptake in short time. But if we pretreat the cells with MSTN for 1h, wash with PBS, and then test the glucose uptake, MSTN could promote the uptake again. The explanation of those outwardly contrary results is: The two kinds of experiments adopted different strategy and object. The glucose uptake experiments are instantaneous, while the glucose consumption assays last for long term, which is a combination effect of several types of glucose transporter.
Our researches try to elucidate the regulation mechanism of MSTN on skeletal muscle glucose metabolism. Its results will provide a new clue on relationship between skeletal muscle and type 2 diabetes or insulin resistance, and also a novel target of diabetes therapy.
葡萄糖消耗试验显示,MSTN可以促进分化的C2C12肌管消耗培养基中的葡萄糖,这种促进细胞吸收葡萄糖的作用与Insulin相似,二者联用时还呈现协同作用。MSTN对糖消耗的促进作用不依赖于血清中的其它激素或因子,而且不是由于MSTN本身的细胞毒性所致。与已分化的肌管不同,MSTN不促进未分化的成肌细胞消耗葡萄糖,这也与Insulin的作用类似。因此,MSTN的降糖效应可能与特异性表达于分化后骨骼肌的GLUT4相关。有趣的是,在进化上完全缺失GLUT4的鸡原代肌管中,Insulin对其糖消耗的促进作用确实明显减弱,但MSTN仍然有明显的促进作用,提示MSTN促进糖消耗作用可能还有其它葡萄糖转运载体参与。
然而在葡萄糖摄取实验中,MSTN短时间内直接抑制糖摄取;但若仅以MSTN预处理1小时则仍可促进糖摄取。这些结果提示MSTN对葡萄糖转运作用的复杂性,因为糖摄取观察瞬时的葡萄糖转运作用,这一过程由骨骼肌中Insulin敏感的GLUT4载体介导,而糖消耗实验时间较长,可能还有其它非Insulin敏感的糖转运载体参与。
综上,本研究揭示了MSTN在控制骨骼肌的增殖、分化之外,还会影响其葡萄糖代谢过程,全面阐明MSTN对骨骼肌糖代谢的调控机制,将为全新认识和界定骨骼肌在胰岛素抵抗和/或2型糖尿病的发生、发展过程中的作用奠定基础,也为将来的糖尿病治疗提供了可能的药物靶点。
Myostatin (MSTN) is a growth factor, which is secreted by skeletal muscle and inhibits the growth and proliferation of skeletal muscle itself. It has a crucial role on the regulation of skeletal muscle homeostasis. Since MSTN can be distributed to the whole body by circulation, its function may not only be limited in skeletal muscle. It has been identified that the adipo-tissue could be regulated by MSTN. The increased expression of Myostatin gene during some diseases progression will cause the degradation of structure proteins in skeletal muscle, and followed by cachexia. Thus, MSTN shouldn't be only consided as a regulator of skeletal muscle mass, but also an endocrine factor, which may participate the regulation of metabolism of lipid and proteins etc.
Our project mainly focused on the affect of MSTN on glucose metabolism in celll culture system. The results of glucose consumption assay show that MSTN could promote the glucose consumption in differentiated C2C2 myotubes. Those promotion effects were similar to Insulin, and the combination of those two drugs could synergize with each other. The function of MSTN on glucose consumption didn't depend on other hormones or factors in the serum, nor relate to the cyto-toxicity of MSTN. Since MSTN couldn't promote the glucose metabolism in undifferentiated myoblasts, its function may rely on the GLUT4, which only appears in differentiated myotubes. The RT-PCR results suggested that MSTN couldn't upregulate the GLUT4 transcription, which indicate that MSTN may have effect on the translocation of GLUT4 from cytosol to cell membrane.
Interestingly, in the GLUT4 deficient chicken myotubes, the promotion effects of Insulin on glucose consumption were not that apparent like in mice, while MSTN's effects were still obviously. Those results indicated that other types of glucose transporter might involve in MSTN's promotion effects on glucose metabolism.
However, the glucose uptake experiments were contradictorily. MSTN could inhibit the glucose uptake in short time. But if we pretreat the cells with MSTN for 1h, wash with PBS, and then test the glucose uptake, MSTN could promote the uptake again. The explanation of those outwardly contrary results is: The two kinds of experiments adopted different strategy and object. The glucose uptake experiments are instantaneous, while the glucose consumption assays last for long term, which is a combination effect of several types of glucose transporter.
Our researches try to elucidate the regulation mechanism of MSTN on skeletal muscle glucose metabolism. Its results will provide a new clue on relationship between skeletal muscle and type 2 diabetes or insulin resistance, and also a novel target of diabetes therapy.
引文
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