What question did this study set out to answer?

The central aim is to understand how cisplatin induces muscle atrophy and the potential involvement of endoplasmic reticulum stress.

February 5, 2026The Journal of Toxicological Sciences1 citationsOpen Access

Potential involvement of the endoplasmic reticulum stress response in the development of cisplatin-induced muscle atrophy

SSShiro SogaKyowa Kirin (Japan)HNHayato NanriHoshi University HSHiroyasu SakaiHoshi University

Key Points

The central aim is to understand how cisplatin induces muscle atrophy and the potential involvement of endoplasmic reticulum stress.
Analyzed the effects of five anticancer agents on mouse skeletal muscle.
Measured quadriceps muscle mass and expression of genes related to protein synthesis, degradation, ER stress, and inflammation.
Compared cisplatin-treated mice with dietary-restricted controls.
Cisplatin-treated mice exhibited a significant decrease in muscle mass despite similar body weight loss.
Cisplatin uniquely upregulated degradation markers MuRF1 and atrogin-1 while downregulating IGF-1.
Cisplatin induced expression of ER stress genes Ddit3, Atf4, and sXbp1 without affecting inflammatory markers.

Abstract

Cancer cachexia, characterized by progressive skeletal muscle loss, is common in advanced malignancies and correlates with poor prognosis. Cisplatin, a widely used chemotherapeutic, is linked to muscle atrophy, but its mechanisms remain unclear. Recent studies implicate endoplasmic reticulum (ER) stress in muscle disorders; however, its role in chemotherapy-induced muscle atrophy is unknown. This study examined the effects of five anticancer agents-cisplatin, 5-fluorouracil, vincristine, irinotecan, and cyclophosphamide-on mouse skeletal muscle. Quadriceps muscle mass, gene expression related to protein synthesis (IGF-1), degradation (MuRF1, atrogin-1), ER stress (Ddit3/CHOP, Atf4, sXbp-1), and inflammation (TNF-α, IL-1β, COX2) were analyzed. Despite similar body weight loss, cisplatin-treated mice showed a significant reduction in muscle mass compared to dietary-restricted controls. Only cisplatin upregulated MuRF1 and atrogin-1 and downregulated IGF-1. Inflammatory markers were unaffected. Notably, cisplatin induced ER stress genes Ddit3, Atf4, and sXbp1. These findings suggest cisplatin promotes muscle atrophy via ER stress activation and protein degradation, independently of reduced food intake or inflammation. Targeting ER stress may help prevent chemotherapy-induced muscle wasting. Further studies are needed to clarify mechanisms and develop protective strategies.

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