AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5
AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5
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DOI：
10.1152/ajpcell.00124.2013
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发表时间：
2013-10-01
影响因子：
5.5
通讯作者：
Du, Min
中科院分区：
文献类型：
--
作者：
Fu, Xing;Zhao, Jun-Xing;Du, Min
肥胖症在全球范围内流行，已知肥胖症会抑制 AMP 激活蛋白激酶 (AMPK) 活性并损害肌生成。肌细胞生成素介导成肌细胞融合成肌管，这是肌生成的关键步骤。我们观察到抑制 AMPK α 1 会下调肌生成素表达和肌生成，但其潜在机制尚不清楚。我们推测 AMPK 通过组蛋白脱乙酰酶 5 (HDAC5) 的磷酸化来调节肌细胞生成素的表达。在 C2C12 细胞中，HDAC5 敲低增加，而 MC1568 稳定 HDAC5 则减少肌生成素表达。一致地，使用荧光素酶测定，我们观察到肌细胞生成素启动子活性受到 HDAC5 的负调节。使用RNA干扰和从野生型和AMPK α 1敲除小鼠制备的原代成肌细胞，我们进一步证明AMPK α 1调节HDAC5 Ser 259和498的磷酸化。HDAC5中这两个Ser到Ala的突变消除了AMPK α 1对肌生成素表达的调节作用，清楚地表明这些磷酸化位点在HDAC5中的必要性。 介导肌生成素的表达。总的来说，这些数据表明，AMPK 抑制通过 HDAC5 磷酸化（主要由 AMPK α 1 介导）下调肌细胞生成素转录和肌肉生成。这些数据表明 AMPK 是促进肌生成和肌肉再生的关键分子靶标。由于激活 AMPK 活性的药物（例如二甲双胍）已广泛使用，因此我们的发现对于确保肥胖受试者以及 AMPK 活性减弱的其他病理生理条件下的正常肌肉发育和再生具有重要的临床意义。
There is a global epidemic of obesity, and obesity is known to inhibit AMP-activated protein kinase (AMPK) activity and impairs myogenesis. Myogenin mediates the fusion of myoblasts into myotubes, a critical step in myogenesis. We observed that inhibition of AMPK alpha 1 downregulates myogenin expression and myogenesis, but the underlying mechanisms are unclear. We postulated that AMPK regulates myogenin expression through phosphorlytion of histone deacetylase 5 (HDAC5). In C2C12 cells, HDAC5 knockdown increased while HDAC5 stablization by MC1568 reduced myogenin expression. Consistently, using luciferase assay, we observed that myogenin promoter activity was negatively regulated by HDAC5. Using RNA interference and primary myoblasts prepared from wild-type and AMPK alpha 1 knockout mice, we further demonstrate that AMPK alpha 1 regulates HDAC5 phosphorylation at Ser 259 and 498. Mutation of these two Ser to Ala in HDAC5 abolished the regulatory role of AMPK alpha 1 on myogenin expression, clearly showing the necessity of these phosphorylation sites in mediating myogenin expression. In aggregate, these data show that AMPK inhibition downregulates myogenin transcription and myogenesis through phosphorylation of HDAC5, mediated mainly by AMPK alpha 1. These data demonstrate that AMPK is a key molecular target for promoting myogenesis and muscular regeneration. Because drugs activating AMPK activity, such as metformin, are widely available, our finding has critical clinical implications to ensure proper muscle development and regeneration in obese subjects and under other pathophysiological conditions where AMPK activity is attenuated.