Reversine ameliorates hallmarks of cellular senescence in human skeletal myoblasts via reactivation of autophagy.
Reversine ameliorates hallmarks of cellular senescence in human skeletal myoblasts via reactivation of autophagy.
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作者：
细胞衰老导致生肌祖细胞的耗竭和再生能力的降低。我们发现，小分子2，6-二取代嘌呤，reversine，可以改善衰老成肌细胞中细胞衰老的一些众所周知的标志。逆转录酶通过上调腺苷一磷酸活化蛋白激酶（AMPK）和Akt 2重新激活自噬和胰岛素信号通路，恢复衰老细胞的胰岛素敏感性和葡萄糖摄取。逆转录酶还恢复了糖酵解与TCA循环的连通性的丧失，从而恢复了功能失调的线粒体和衰老成肌细胞受损的成肌分化潜能。总而言之，我们的数据表明，细胞衰老可以通过单一小分子治疗而逆转，而无需采用遗传重编程技术。我们的研究结果表明，用reversine短期治疗衰老的成肌细胞可以恢复胰岛素抵抗，增强葡萄糖代谢和氧化磷酸化，可能是通过自噬的重新激活。在逆转录酶处理的细胞中，恢复DNA损伤和异染色质状态先于恢复增殖、SA-β-Gal表达和细胞大小，最终恢复成肌细胞形成肌纤维的分化能力。因此，reversine可能有潜力被用作一种新的抗衰老治疗方法，而不会产生遗传重编程技术的致瘤并发症。
Cellular senescence leads to the depletion of myogenic progenitors and decreased regenerative capacity. We show that the small molecule 2,6‐disubstituted purine, reversine, can improve some well‐known hallmarks of cellular aging in senescent myoblast cells. Reversine reactivated autophagy and insulin signaling pathway via upregulation of Adenosine Monophosphate‐activated protein kinase (AMPK) and Akt2, restoring insulin sensitivity and glucose uptake in senescent cells. Reversine also restored the loss of connectivity of glycolysis to the TCA cycle, thus restoring dysfunctional mitochondria and the impaired myogenic differentiation potential of senescent myoblasts. Altogether, our data suggest that cellular senescence can be reversed by treatment with a single small molecule without employing genetic reprogramming technologies. Our results suggest that short‐term treatment of senescent myoblasts with reversine could restore insulin resistance, enhance glucose metabolism and oxidative phosphorylation, likely via reactivation of autophagy. Restoring DNA damage and the state of heterochromatin preceded restoration of proliferation, SA‐β‐Gal expression, and cell size in reversine‐treated cells, ultimately restoring the differentiation ability of myoblasts to form myofibers. Therefore, reversine may have the potential to be used as a novel, anti‐aging treatment, without the tumorigenic complications of genetic reprogramming technologies.
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