Ranolazine promotes muscle differentiation and reduces oxidative stress in C2C12 skeletal muscle cells
Ranolazine promotes muscle differentiation and reduces oxidative stress in C2C12 skeletal muscle cells
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DOI：
10.1007/s12020-016-1181-5
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发表时间：
2017-10-01
期刊：
影响因子：
3.7
通讯作者：
Livio, Luzi
中科院分区：
文献类型：
--
作者：
Ileana, Terruzzi;Anna, Montesano;Livio, Luzi
本研究的目的是探讨雷诺拉秦对骨骼肌分化和线粒体氧化现象的作用。雷诺拉秦是一种抗心绞痛药物，可以阻断晚期心绞痛电流，研究表明它可以降低糖尿病患者的血红蛋白A1c。在本研究中，我们假设雷诺嗪在骨骼肌细胞再生和氧化过程中的作用，导致胰岛素抵抗的减少。在C2C12小鼠成肌细胞的增殖、分化和新形成的肌管中加入10亩M雷诺嗪。雷诺嗪促进一种特定的肌源性表型的发展：增加成肌调节因子的表达，抑制细胞周期推进因子(P21)的表达。雷诺嗪刺激钙信号转导(钙调素依赖的激酶)并降低活性氧水平。此外，雷诺拉秦还维持了线粒体的动态平衡。在分化阶段，雷诺拉秦促进肌管的形成。雷诺嗪不改变参与骨骼肌分化和葡萄糖摄取的激酶(细胞外信号调节激酶1/2和AKT通路)，但激活钙信号通路。在细胞增殖过程中，雷诺拉秦不改变线粒体的数量，同时降低骨桥蛋白的水平。最后，雷诺拉秦处理的新生肌管表现出典型的肥大表型。综上所述，我们的结果表明雷诺拉秦刺激了肌细胞的发生，并减轻了促氧化的炎症/氧化状态，激活了钙信号通路。这些新描述的机制可能部分解释了该药物的降糖作用。
The purpose of this study is to investigate Ranolazine action on skeletal muscle differentiation and mitochondrial oxidative phenomena. Ranolazine, an antianginal drug, which acts blocking the late INaL current, was shown to lower hemoglobin A1c in patients with diabetes. In the present study, we hypothesized an action of Ranolazine on skeletal muscle cells regeneration and oxidative process, leading to a reduction of insulin resistance.10 mu M Ranolazine was added to C2C12 murine myoblastic cells during proliferation, differentiation and newly formed myotubes.Ranolazine promoted the development of a specific myogenic phenotype: increasing the expression of myogenic regulator factors and inhibiting cell cycle progression factor (p21). Ranolazine stimulated calcium signaling (calmodulin-dependent kinases) and reduced reactive oxygen species levels. Furthermore, Ranolazine maintained mitochondrial homeostasis. During the differentiation phase, Ranolazine promoted myotubes formation. Ranolazine did not modify kinases involved in skeletal muscle differentiation and glucose uptake (extracellular signal-regulated kinases 1/2 and AKT pathways), but activated calcium signaling pathways. During proliferation, Ranolazine did not modify the number of mitochondria while decreasing osteopontin protein levels. Lastly, neo-formed myotubes treated with Ranolazine showed typical hypertrophic phenotype.In conclusion, our results indicate that Ranolazine stimulates myogenesis and reduces a pro-oxidant inflammation/oxidative condition, activating a calcium signaling pathway. These newly described mechanisms may partially explain the glucose lowering effect of the drug.