Insulin-like effect of the phosphodiesterase type 5 inhibitor tadalafil onto male human skeletal muscle cells
Insulin-like effect of the phosphodiesterase type 5 inhibitor tadalafil onto male human skeletal muscle cells
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DOI：
10.3275/9034
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发表时间：
2013-12-01
影响因子：
5.4
通讯作者：
Di Luigi, L.
中科院分区：
文献类型：
--
作者：
Crescioli, C.;Sturli, N.;Di Luigi, L.
背景资料：广泛用于治疗男性勃起功能障碍的磷酸二酯酶5型抑制剂（PDE 5i）似乎可以抵消动物和人类的胰岛素抵抗（IR）。IR主要表现在外周组织，特别是骨骼肌，是由于受损的胰岛素信号转导。研究人员一直专注于负责IR的细胞内缺陷，以确定针对特定缺陷的合适的药理学工具。尽管已经报道了PDE 5i对动物肌肉组织或细胞的一些影响，但它们是否以及如何直接影响人类骨骼肌的代谢过程仍不清楚。目的：本研究旨在探讨PDE 5 i之一的他达拉非（tadalafil）对人胎儿骨骼肌细胞（Hfsmc）内与胰岛素应答有关的细胞因子如ras-raf丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇3-激酶/蛋白激酶B（PKB/Akt）、糖原合成酶激酶3 β（GCK）、胰岛素敏感性蛋白激酶（MAPK）、胰岛素敏感性蛋白激酶（PKB）、胰岛素敏感性蛋白激酶（PKB）和胰岛素敏感性蛋白激酶（PKB）的影响。（GSK-3 β）和转录因子c-Myc;增殖速率;乳酸（lact）和游离脂肪酸（ffa）释放;柠檬酸合酶（CS）和琥珀酸脱氢酶（SDH）的活性，这两种酶都是Kreb循环的酶; PDE 5基因表达。材料与方法：采用Western blot分析、酶联免疫吸附试验、酶法、细胞计数、MTT法和真实的实时PCR法检测他达拉非对HFSMC的作用。结果如下：在Hfsmc中，他达拉非通过增加MAPK、PKB/Akt、GSK-3 β磷酸化和c-Myc表达影响胰岛素相关的细胞内级联反应。FFA释放和CS活性也显著增加，而SDH活性和乳酸释放无变化。结论：他达拉非，像胰岛素一样，靶向人体骨骼肌细胞中专门用于能量管理和代谢控制的部分机制。(C)2013年，Editrice Kurtis
Background: Phosphodiesterase type 5 inhibitors (PDE5i), widely used to treat male erectile dysfunction, seem to counteract insulin resistance (IR) in animals and humans. IR, primarily manifest in peripheral tissues and particularly in skeletal muscle, is due to impaired insulin signal transduction. Investigators have been focusing onto intracellular defects responsible for IR to identify suitable pharmacological tools targeted toward the specific defects. Albeit some effects of PDE5i have been reported onto animal muscular tissues or cells, whether and how they might affect metabolic processes directly in human skeletal muscle still remains unclear. Aim: We aimed to investigate in human fetal skeletal muscle cells (Hfsmc) the effect of tadalafil, one of PDE5i, onto some intracellular factors involved in response to insulin, such as ras-raf mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PKB/Akt), glycogen synthase kinase 3 beta (GSK-3 beta), and the transcriptional factor c-Myc; proliferation rate; lactate (lact) and free fatty acid (ffa) release; activity of citrate synthase (CS) and succinate dehydrogenase (SDH), both enzymes of Kreb's cycle; PDE5 gene expression. Materials and methods: Western blot analysis, enzyme-linked immunosorbent assay, enzymatic assays, cell count, MTT assay and Real Time PCR were performed in Hfsmc with and without tadalafil. Results: In Hfsmc tadalafil affected the insulin-related intracellular cascade, by increasing MAPK, PKB/Akt, GSK-3 beta phosphorylation and c-Myc expression. ffa release and CS activity also significantly increased, with no changes in SDH activity and lact release. Conclusions: Tadalafil, like insulin, targeted part of the machinery dedicated to energy management and metabolic control in human skeletal muscle cells. (C) 2013, Editrice Kurtis