Protein homeostasis disruption in cisplatin-induced skeletal muscle atrophy: toxicological insights from experimental...

Cisplatin is a widely used platinum-based chemotherapeutic agent whose dose-limiting toxicities, including nephrotoxicity, neurotoxicity, and myelosuppression, have been extensively characterized. In contrast, skeletal muscle has not traditionally been regarded as a primary target of cisplatin toxicity. However, accumulating experimental evidence indicates that cisplatin administration leads to a significant reduction in skeletal muscle mass and fiber size, even in the absence of tumor burden or overt cachexia. These findings suggest that cisplatin itself can directly induce skeletal muscle atrophy as a form of drug-induced toxicity. Animal and cell-based studies have demonstrated that cisplatin activates catabolic signaling in skeletal muscle, most notably through enhanced protein degradation via the ubiquitin-proteasome system. This response is accompanied by increased expression of muscle-specific E3 ubiquitin ligases, including muscle RING finger 1 (MuRF1) and muscle atrophy F-box protein (MAFbx/atrogin-1), which are established mediators of skeletal muscle atrophy. In parallel, suppression of anabolic signaling, particularly impairment of the insulin-like growth factor-1/Akt/mechanistic target of rapamycin complex 1 (mTORC1) pathway, has been reported, indicating a shift in muscle protein turnover toward a catabolic state. Recent studies suggest that cellular stress responses, such as endoplasmic reticulum stress, may be involved in regulating these processes. This review summarizes experimental evidence supporting cisplatin-induced skeletal muscle atrophy and discusses the underlying toxicological processes from a muscle-centered perspective. By distinguishing drug-induced muscle toxicity from cancer cachexia and other wasting conditions, we propose that skeletal muscle should be recognized as a clinically relevant but underestimated target organ of cisplatin toxicity. Improved understanding of these processes may support the development of strategies to preserve muscle mass and function during cancer chemotherapy.