[骨骼肌特异性敲除ACSL1基因可改善顺铂诱导的骨骼肌萎缩]

摘要(中文译文)

本研究旨在探索长链酰基辅酶A合成酶1(ACSL1)在顺铂诱导的骨骼肌萎缩中的作用及其潜在机制。将野生型小鼠分为顺铂组和对照组。荧光定量PCR和参考转录组测序结果显示，与对照组相比，顺铂组小鼠骨骼肌中ACSL1基因显著上调，提示ACSL1可能在顺铂诱导的骨骼肌萎缩中发挥关键作用。为进一步探究ACSL1的功能及潜在机制，本研究构建腺相关病毒以实现肌肉特异性ACSL1敲低，并建立顺铂诱导的骨骼肌萎缩模型。免疫荧光染色结果显示，与仅接受顺铂干预的小鼠相比，接受ACSL1基因敲低联合顺铂干预的小鼠骨骼肌肌纤维横截面积、最大直径、最小直径及平均直径均显著增加。RT-qPCR和免疫组化染色结果显示，在顺铂诱导的骨骼肌萎缩中，骨骼肌ACSL1基因敲低可下调萎缩相关基因1(Atrogin-1)及自噬相关因子如自噬相关蛋白16样蛋白1(Atg16L1)、Atg12和Atg7的mRNA表达水平，上调肌细胞生成素的蛋白表达水平，并下调Toll样受体4(TLR4)蛋白表达水平，但对铁死亡相关因子(除环氧合酶-2外)及炎症相关因子如干扰素基因刺激因子(STING)、Toll样受体4(TLR4)和TLR9的mRNA表达水平无显著影响。上述结果提示，骨骼肌特异性敲低ACSL1基因可能通过下调Atrogin-1、TLR4及自噬相关因子的表达来减轻顺铂诱导的骨骼肌萎缩。

Abstract

The aim of this study was to explore the role of long-chain acyl-CoA synthetase 1 (ACSL1) in cisplatin-induced skeletal muscle atrophy and the underlying mechanism. Wild-type mice were divided into cisplatin group and control group. The results of fluorescence quantitative PCR and sequencing of reference transcriptome showed that ACSL1 gene was significantly up-regulated in the skeletal muscle of cisplatin group compared with the control group, suggesting that ACSL1 may play a key role in cisplatin-induced skeletal muscle atrophy. To further investigate ACSL1's function and potential mechanism, the present study constructed an adeno-associated virus to achieve muscle-specific ACSL1 knockdown and established a cisplatin-induced skeletal muscle atrophy model. The results of immunofluorescence staining showed that compared with mice only receiving cisplatin intervention, mice receiving ACSL1 gene knockdown and cisplatin intervention had significantly increased muscle fiber cross-sectional area, maximum diameter, minimum diameter, and average diameter in their skeletal muscles. The results of RT-qPCR and immunohistochemical staining showed that knockdown of the ACSL1 gene in skeletal muscle down-regulated the mRNA expression levels of atrophy related gene 1 (Atrogin-1) and autophagy-related factors such as autophagy related protein 16 like protein 1 (Atg16L1), Atg12, and Atg7 in cisplatin-induced skeletal muscle atrophy, up-regulated the protein expression level of myogenin, and down-regulated Toll-like receptor 4 (TLR4) protein expression level, but had no significant effect on the mRNA expression levels of ferroptosis-related factors (except for cyclooxygenase-2) and inflammation-related factors such as stimulator of interferon genes (STING), Toll-like receptor 4 (TLR4) and TLR9 in cisplatin-induced skeletal muscle atrophy. These results suggest that specific knockdown of ACSL1 gene in skeletal muscle may alleviate cisplatin-induced skeletal muscle atrophy by down-regulating the expression of Atrogin-1, TLR4 and autophagy-related factors.

如何引用

Sheng li xue bao : [Acta physiologica Sinica] 的其他文献

• [白细胞介素-18对CD4+PD-1+T细胞的影响可能与免疫性血小板减少症的发病机制有关]
• [运动通过骨-脂肪交互作用改善骨质疏松症]
• [巨噬细胞在败血症诱导的心肌病发病机制和治疗中的作用研究进展]
• 【自噬调节因子mTOR在肾缺血再灌注损伤中的作用和机制】
• [非编码RNA介导的PI3K/AKT/mTOR信号通路调节参与三阴性乳腺癌症发病和进展的最新进展]
• [脑缺血再灌注损伤中线粒体跨细胞转移的机制]
• [酒精使用障碍诱导痛觉过敏的神经机制研究进展]