Department of Biomedical Sciences and Biotechnologies, Unit of Biochemistry, Faculty of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
Toxicol Appl Pharmacol. 2011 Feb 1;250(3):312-21. doi: 10.1016/j.taap.2010.11.003. Epub 2010 Nov 11.
Cisplatin (cisPt) is an antineoplastic drug which causes an array of adverse effects on different organs and tissues, including skeletal muscle. In this work we show that cisPt behaves as a potent trigger to activate protein hypercatabolism in skeletal C2C12 myotubes. Within 24h of 50 μM cisPt administration, C2C12 myotubes displayed unchanged cell viability but showed a subset of hallmark signs typically recognized during atrophy, including severe reduction in body size, repression of Akt phosphorylation, transcriptional up-regulation of atrophy-related genes, such as atrogin-1, gabarap, beclin-1 and bnip-3, and loss of myogenic markers. As a consequence, proteasomal activity and formation of autophagosomes were remarkably increased in cisPt-treated myotubes, but forced stimulation of Akt pathway, as obtained through insulin administration or delivery of a constitutively activated Akt form, was sufficient to counter the cisPt-induced protein breakdown, leading to rescue of atrophic size. Overall, these results indicate that cisPt induces atrophy of C2C12 myotubes via activation of proteasome and autophagy systems, suggesting that the Akt pathway represents one sensitive target of cisPt molecular action in skeletal muscle.
顺铂（cisPt）是一种抗肿瘤药物，会对包括骨骼肌在内的不同器官和组织造成一系列不良反应。在这项工作中，我们发现 cisPt 可作为一种强效触发物，激活骨骼肌 C2C12 肌管中的蛋白质过度分解。在给予 50μM cisPt 后的 24 小时内，C2C12 肌管的细胞活力没有变化，但表现出萎缩过程中通常识别的一组标志性特征，包括体积严重减小、Akt 磷酸化受抑制、萎缩相关基因（如atrogin-1、gabarap、beclin-1 和 bnip-3）转录上调，以及肌生成标志物丢失。结果，cisPt 处理的肌管中蛋白酶体活性和自噬体形成显著增加，但通过胰岛素给药或递送组成型激活的 Akt 形式强制刺激 Akt 途径足以抵消 cisPt 诱导的蛋白质分解，导致萎缩体积得以恢复。总的来说，这些结果表明 cisPt 通过激活蛋白酶体和自噬系统诱导 C2C12 肌管萎缩，表明 Akt 途径是 cisPt 在骨骼肌中分子作用的一个敏感靶点。
