Andrographolide promotes skeletal muscle regeneration after acute injury through epigenetic modulation
Andrographolide promotes skeletal muscle regeneration after acute injury through epigenetic modulation
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穿心莲内酯通过表观遗传调节促进急性损伤后骨骼肌再生
DOI：
10.1016/j.ejphar.2020.173470
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发表时间：
2020
影响因子：
5
通讯作者：
Wang Yong
中科院分区：
文献类型：
--
作者：
Wu Ziqiang;Xu Huan;Xu Yiming;Fan Weichuan;Yao Huan;Wang Yang;Hu Wangming;Lou Guanhua;Shi Yaping;Chen Xiongbing;Yang Lan;Wen Li;Xiao Han;Wang Baojia;Yang Youjun;Liu Weiming;Meng Xianli;Wang Yong
肌病是一种肌肉纤维不能正常发挥功能的肌肉疾病，最终导致严重的疾病，例如肌营养不良。骨骼肌的正确再生对于肌肉损伤后维持肌肉功能起着关键作用。本研究的目的是确定穿心莲内酯是否在调节骨骼肌再生中发挥作用。采用小鼠卫星细胞、C2C12细胞和心毒素（CTX）肌肉注射诱导的急性骨骼肌损伤模型来评价穿心莲内酯是否对骨骼肌再生至关重要。使用免疫组织化学染色、蛋白质印迹、实时PCR检测其基本机制。穿心莲内酯促进小鼠骨骼肌再生。在心脏毒素诱导的骨骼肌损伤模型中，穿心莲内酯治疗增强了肌管的生成并促进了肌管的融合。穿心莲内酯治疗显着增加了肌管分化相关基因的表达，包括 Desmin、MyoD、MyoG、Myomaker、Tnni2、Dmd、Myoz1 和 Myoz3。对于机制研究，我们观察到穿心莲内酯处理在体内和体外均显着促进组蛋白修饰，例如 H3K4Me2、H3K4Me3 和 H3K36Me2。使用赖氨酸甲基转移酶 EZH2 抑制剂 DZNep 进行治疗，可显着减弱穿心莲内酯诱导的 Myf5、Myomaker、骨骼肌 α-肌动蛋白、MyoD 和 MyoG 的表达。综上所述，我们在本研究中的数据表明，穿心莲内酯可表观遗传地驱动肌管的分化和融合，最终促进骨骼肌再生。这应该是肌肉损伤后骨骼肌再生的治疗方法。
Myopathy is a muscle disease in which muscle fibers do not function properly, and eventually cause severe diseases, such as muscular dystrophy. The properly regeneration of skeletal muscle plays a pivotal role to maintain the muscle function after muscle injury. The aim of this study is to determine whether andrographolide plays an effect role on regulating skeletal muscle regeneration.Mouse satellite cells, C2C12 cells and Cardiotoxin (CTX) intramuscular injection induced acute skeletal muscle injury model were used to evaluate whether andrographolide is essential for skeletal muscle regeneration. The underling mechanism detected using immunohistochemistry stain, western blot, real time PCR.Andrographolide promotes mouse skeletal muscle regeneration. In cardiotoxin induced skeletal muscle injury model, andrographolide treatment enhanced myotube generation and promoted myotube fusion. Andrographolide treatment dramatically increased expression of myotube differentiation related genes, including Desmin, MyoD, MyoG, Myomaker, Tnni2, Dmd, Myoz1 and Myoz3. For the mechanism studies, we observed that andrographolide treatment significantly promoted histone modification, such as H3K4Me2, H3K4Me3 and H3K36Me2, both in vivo and in vitro. Treatment with DZNep, a Lysine methyltransferase EZH2 inhibitor, significantly attenuated andrographolide-induced expression of Myf5, Myomaker, Skeletal muscle α-actin, MyoD and MyoG.Taken together, our data in this study demonstrate andrographolide epigenetically drives differentiation and fusion of myotube, eventually promotes skeletal muscle regeneration. This should be a therapeutic treatment for skeletal muscle regeneration after muscle damage.