Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C2C12 myocytes
Ambient glucose levels qualify the potency of insulin myogenic actions by regulating SIRT1 and FoxO3a in C2C12 myocytes
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DOI：
10.1152/ajpendo.00640.2007
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发表时间：
2008-04-01
影响因子：
5.1
通讯作者：
Kanzaki, Makoto
中科院分区：
文献类型：
--
作者：
Nedachi, Taku;Kadotani, Akito;Kanzaki, Makoto
营养供应是影响细胞命运的主要环境信号之一，如增殖、分化和凋亡，通常与其他体液因子（包括胰岛素）一起发挥作用。在此，我们发现，低血清诱导的C2 C12肌细胞分化在低葡萄糖（LG; 5 mM）与高葡萄糖（HG; 22.5 mM）条件相比，显着受阻，同时与核积累的SIRT 1，NAD（+）依赖性脱乙酰酶，和FoxO 3a，这两者都是在负调控的肌发生。有趣的是，胰岛素似乎发挥相反的作用，这取决于葡萄糖的可用性，关于SIRT 1和FoxO 3a丰度的调节，这显然有助于调节胰岛素的肌原性作用的效力。也就是说，胰岛素在足够的葡萄糖存在下发挥有效的生肌作用，而胰岛素在LG条件下不能发挥其生肌作用，因为胰岛素在缺乏足够的环境葡萄糖的情况下引起SIRT 1和FoxO 3a的大量上调。此外，LG下的分化受阻状态被SIRT 1抑制剂sirtinol显著恢复，而胰岛素则消除了这种sirtinol依赖性恢复，表明胰岛素可以根据葡萄糖的可用性作为负性和正性肌生成因子发挥作用。总之，我们的数据揭示了环境葡萄糖水平在肌生成调节中的重要性，以及在胰岛素的肌生成效力的测定中的重要性，这至少部分是通过调节细胞内容物和胰岛素的分泌来实现的。
Nutrition availability is one of the major environmental signals influencing cell fate, such as proliferation, differentiation, and apoptosis, often functioning in concert with other humoral factors, including insulin. Herein, we show that low-serum-induced differentiation of C2C12 myocytes is significantly hampered under low glucose (LG; 5 mM) compared with high glucose (HG; 22.5 mM) conditions, concurrently with nuclear accumulation of SIRT1, an NAD(+)-dependent deacetylase, and FoxO3a, both of which are implicated in the negative regulation of myogenesis. Intriguingly, insulin appears to exert opposite actions, depending on glucose availability, with regard to the regulation of SIRT1 and FoxO3a abundance, which apparently contributes to modulating the potency of insulin's myogenic action. Namely, insulin exerts a potent myogenic effect in the presence of sufficient glucose, whereas insulin is unable to exert its myogenic action under LG conditions, since insulin evokes massive upregulation of both SIRT1 and FoxO3a in the absence of sufficient ambient glucose. In addition, the hampered differentiation state under LG is significantly restored by sirtinol, a SIRT1 inhibitor, whereas insulin abolished this sirtinol-dependent restoration, indicating that insulin can function as a negative as well as a positive myogenic factor depending on glucose availability. Taken together, our data reveal the importance of ambient glucose levels in the regulation of myogenesis and also in the determination of insulin's myogenic potency, which is achieved, at least in part, through regulation of the cellular contents and