ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.

Abstract

Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by various adverse effects. Although skeletal muscle loss during chemotherapy is often attributed to cachexia or generalized wasting, accumulating evidence indicates that cisplatin directly induces skeletal muscle atrophy. However, the underlying cellular stress responses and signaling pathways remain unclear. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress and translational regulation in cisplatin-induced skeletal muscle atrophy, focusing on DNA damage-inducible transcript 4/Regulated in development and DNA damage response-1 (Ddit4/REDD1), a stress-responsive inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Using a mouse model and differentiated C2C12 myotubes, we examined ER stress signaling, protein synthesis, and mTORC1 activity following cisplatin treatment, and evaluated the effects of tauroursodeoxycholic acid (TUDCA), an ER stress-suppressing chemical chaperone. Cisplatin induced skeletal muscle atrophy accompanied by ER stress activation and suppression of protein synthesis in mice. TUDCA significantly attenuated muscle mass and strength loss without affecting body weight reduction. Cisplatin upregulated ER stress-responsive genes and decreased phosphorylation of p70 S6 kinase, whereas these changes were suppressed by TUDCA. Pharmacological ER stress induction increased Ddit4/REDD1 expression, and PERK inhibition reduced cisplatin-induced Ddit4/REDD1 upregulation in C2C12 myotubes. Furthermore, Ddit4/REDD1 knockdown partially restored protein synthesis and mTORC1 signaling. These findings indicate that cisplatin induces skeletal muscle atrophy via ER stress-associated translational suppression, at least partly through Ddit4/REDD1-mediated inhibition of mTORC1.