Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt
Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt
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DOI：
10.1016/j.devcel.2008.02.004
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发表时间：
2008-05-01
影响因子：
11.8
通讯作者：
Sartorelli, Vittorio
中科院分区：
文献类型：
--
作者：
Fulco, Marcella;Cen, Yana;Sartorelli, Vittorio
凭直觉推测，营养物质的可利用性可能会影响哺乳动物细胞的分化。然而，这一过程中所涉及的分子决定因素的全貌尚未阐明。在此，我们研究了营养物质（葡萄糖）如何影响骨骼肌生成。葡萄糖限制（GR）损害了骨骼肌成肌细胞的分化，并与AMP活化蛋白激酶（AMPK）的激活相关。激活的AMPK是促进GR诱导的NAD(+)生物合成酶Nampt转录所必需的。实际上，GR增强了Nampt的活性，这进而改变了细胞内[NAD +] : [NADH]的比例和烟酰胺水平，并介导了对骨骼肌生成的抑制。源自SIRT1（-/-）杂合小鼠的骨骼肌成肌细胞对GR或AMPK激活的影响具有抗性。这些实验表明，AMPK、Nampt和SIRT1是一个功能性信号通路的分子组成部分，该通路使骨骼肌细胞能够感知营养物质的可利用性并作出反应。
It is intuitive to speculate that nutrient availability may influence differentiation of mammalian cells. Nonetheless, a comprehensive complement of the molecular determinants involved in this process has not been elucidated yet. Here, we have investigated how nutrients (glucose) affect skeletal myogenesis. Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). Activated AMPK was required to promote GR-induced transcription of the NAD(+) biosynthetic enzyme Nampt. Indeed, GR augmented the Nampt activity, which consequently modified the intracellular [NAD+]:[NADH] ratio and nicotinamide levels, and mediated inhibition of skeletal myogenesis. Skeletal myoblasts derived from SIRT1(-/-) heterozygous mice were resistant to the effects of either GR or AMPK activation. These experiments reveal that AMPK, Nampt, and SIRT1 are the molecular components of a functional signaling pathway that allows skeletal muscle cells to sense and react to nutrient availability.