Catalpol counteracts the pathology in a mouse model of Duchenne muscular dystrophy by inhibiting the TGF-β1/TAKl signaling pathway
Catalpol counteracts the pathology in a mouse model of Duchenne muscular dystrophy by inhibiting the TGF-β1/TAKl signaling pathway
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梓醇通过抑制 TGF-β1/TAKl 信号通路来抵消杜氏肌营养不良症小鼠模型的病理学
DOI：
10.1038/s41401-020-00515-1
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发表时间：
2021
影响因子：
8.2
通讯作者：
Jiang Zhenzhou
中科院分区：
文献类型：
--
作者：
Xu Dengqiu;Zhao Lei;Li Sijia;Huang Xiaofei;Li Chunjie;Sun Lixin;Li Xihua;Zhang Luyong;Jiang Zhenzhou
杜氏肌营养不良症（DMD）是一种由编码肌营养不良蛋白的基因突变引起的进行性神经肌肉疾病。梓醇是一种环烯醚萜苷，存在于中草药中，具有抗炎、抗氧化、抗细胞凋亡和降血糖的作用，可以防止肌肉萎缩。在本研究中，我们研究了梓醇对DMD的影响。用100、200 mg·kg~（-1）·d~(-1)， ig的梓醇治疗老年抗肌营养不良（mdx）小鼠6周。实验结束时，处死小鼠，收集腓肠肌（GAS）、胫前肌（TA）、指长伸肌（EDL）、比目鱼肌（SOL）。在步态试验中，我们发现梓醇给药剂量依赖性地增加了步幅长度，减少了步幅宽度。抓丝试验表明，抓丝时间和抓丝强度均有所增加。我们发现梓醇剂量依赖性地减轻了骨骼肌损伤，这可以通过降低血浆CK和LDH活性以及增加骨骼肌重量来证明。梓醇对肌营养不良蛋白表达无影响，但有抗炎作用。此外，梓醇剂量依赖性地减少了胫骨前肌（TA）纤维化，抑制TGF-β1、TAK1和α-SMA的表达。在mdx小鼠的原代成肌细胞中，敲低TAK1可消除梓醇对tgf -β1和α-SMA表达水平的抑制作用。由此可见，梓醇能恢复老年mdx小鼠骨骼肌力量，减轻骨骼肌损伤，可能为DMD提供一种新的治疗方法。梓醇通过抑制TGF-β1/TAK1信号通路减轻肌肉纤维化。
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by a mutation in the gene encoding the dystrophin protein. Catalpol is an iridoid glycoside found in Chinese herbs with anti-inflammatory, anti-oxidant, anti-apoptotic, and hypoglycemic activities that can protect against muscle wasting. In the present study we investigated the effects of catalpol on DMD. Aged Dystrophin-deficient (mdx) mice (12 months old) were treated with catalpol (100,200 mg·kg~(-1)·d~(-1), ig) for 6 weeks. At the end of the experiment, the mice were sacrificed, and gastrocnemius (GAS), tibialis anterior (TA), extensor digitorum longus (EDL), soleus (SOL) muscles were collected. We found that catalpol administration dose-dependently increased stride length and decreased stride width in Gait test. Wire grip test showed that the time of wire grip and grip strength were increased. We found that catalpol administration dose-dependently alleviated skeletal muscle damage, evidenced by reduced plasma CK and LDH activity as well as increased the weight of skeletal muscles. Catalpol administration had no effect on dystrophin expression, but exerted anti-inflammatory effects. Furthermore, Catalpol administration dose-dependently decreased tibialis anterior (TA) muscle fibrosis, and inhibited the expression of TGF-β1, TAK1 and α-SMA. In primary myoblasts from mdx mice, knockdown of TAK1 abolished the inhibitory effects of catalpol on the expression levels ofTGF-β1 and α-SMA. In conclusion, catalpol can restore skeletal muscle strength and alleviate skeletal muscle damage in aged mdx mice, thus may provide a novel therapy for DMD. Catalpol attenuates muscle fibrosis by inhibiting the TGF-β1/TAK1 signaling pathway.