Cisplatin-associated transcriptional changes in ER stress-related genes in skeletal muscle and C2C12 myotubes

Cisplatin is a widely used chemotherapeutic drug that causes severe side effects, including skeletal muscle atrophy; however, the cellular responses of skeletal muscle to cisplatin exposure remain incompletely characterized. This study aimed to comparatively characterize cisplatin-associated transcriptional responses in skeletal muscle in vivo and in vitro. Male mice receiving intraperitoneal cisplatin administration (3 mg/kg/day for four consecutive days) exhibited significant quadriceps muscle loss on day 4, accompanied by increased expression of the muscle-specific ubiquitin ligase genes MuRF1 and atrogin-1. Consistently, cisplatin-treated C2C12 myotubes showed elevated mRNA expression of these atrophy-related genes. In addition, multiple endoplasmic reticulum (ER) stress-related genes, including Ddit3/CHOP, Atf4, Hspa5/Bip, and Ppp1r15a/GADD34, were significantly upregulated in both models. Notably, the spliced form of Xbp1 was differentially regulated, being increased in mouse skeletal muscle but decreased in C2C12 myotubes, indicating model-dependent ER stress-associated transcriptional responses. These findings demonstrate that cisplatin exposure is associated with coordinated changes in atrophy- and ER stress-related gene expression in skeletal muscle and highlight important differences between in vivo and in vitro models that should be considered when evaluating cisplatin-associated skeletal muscle toxicity.