Donepezil, an anti-Alzheimer's disease drug, promotes differentiation and regeneration in injured skeletal muscle through the elevation of the expression of myogenic regulatory factors
Donepezil, an anti-Alzheimer's disease drug, promotes differentiation and regeneration in injured skeletal muscle through the elevation of the expression of myogenic regulatory factors
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DOI：
10.1016/j.ejphar.2021.174528
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发表时间：
2021-10-04
影响因子：
5
通讯作者：
Sato，Takayuki
中科院分区：
文献类型：
--
作者：
Todaka，Hiroshi;Arikawa，Mikihiko;Sato，Takayuki
我们此前证明，抗阿尔茨海默病药物多奈哌齐通过促进血管内皮细胞的生成和激活卫星细胞的增殖，在外周动脉疾病的小鼠模型中改善骨骼肌萎缩。然而，多奈哌齐在再生过程中对肌肉分化的影响仍不清楚。因此，我们检测了多奈哌齐诱导C2C12成肌细胞分化前后成肌调节因子和晚期肌肉分化标志物的表达。结果表明，在分化条件下，多奈哌齐处理的细胞肌球蛋白重链(MyHC)、肌钙蛋白T(TnT)和肌生成素(Mygenin)的表达显著增加，肌管形成加快。然而，多奈哌齐对肌肉分化的促进作用不能被添加乙酰胆碱(ACh)所复制，也不能被ACh受体阻断剂所阻断。此外，其他种类的乙酰胆碱酯酶抑制剂未能促进C2C12神经细胞的肌肉分化。这些结果表明多奈哌齐促进肌肉分化的特性不依赖于其对乙酰胆碱酯酶的抑制作用。我们进一步发现，在心脏毒素损伤的小鼠模型中，多奈哌齐诱导了肌纤维横截面积的增加，并增加了肌生成素、TNT和MyHC的表达。这些结果提示多奈哌齐通过上调肌源性调节因子和晚期肌肉分化标志物的表达来促进损伤后肌肉再生的分化。我们的研究结果表明，多奈哌齐可作为骨骼肌损伤治疗的有效药物。
We previously demonstrated that donepezil, an anti-Alzheimer's disease drug, improved skeletal muscle atrophy by enhancing the angiogenesis of endothelial cells and activating the proliferation of satellite cells in a mouse model of peripheral arterial disease. However, the effect of donepezil on muscle differentiation during regeneration remains unclear. Therefore, we measured the expressions of myogenic regulatory factors and late muscle differentiation markers in donepezil-treated C2C12 myoblast cells before and after the induction of cell differentiation. The results indicate that the expressions of myogenin, troponin T (TnT) and myosin heavy chain (MyHC) were significantly increased and myotube formation was accelerated in donepezil-treated cells under the differentiation condition. However, the promotive effect of donepezil on muscle differentiation could not be reproduced by the addition of acetylcholine (ACh) and was not disrupted after treatment with ACh receptor blockers. Moreover, other kinds of acetylcholinesterase inhibitors failed to promote muscle differentiation in C2C12 cells. These results indicate that the specific characteristics of donepezil in the promotion of muscle differentiation are independent of its acetylcholinesterase-inhibitory action. We further found that donepezil induced an incremental shift of the cross-sectional area of myofibers and elevated the expressions of myogenin, TnT and MyHC in a mouse model of cardiotoxin injury. These results suggest that donepezil promotes the differentiation of muscle regeneration upon injury via the elevation of the expressions of myogenic regulatory factors and late muscle differentiation markers. Our findings suggest that donepezil can be a useful therapeutic agent for injured skeletal muscle treatment.