Paeonia lactiflora extract suppresses cisplatin-induced muscle wasting via downregulation of muscle-specific ubiquitin E3 ligases, NF-κB signaling, and cytokine levels.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE The dried root of Paeonia lactiflora Pall. (Radix Paeoniae) has been traditionally used to treat various inflammatory diseases in many Asian countries. AIM OF THE STUDY Cisplatin is a broad-spectrum anticancer drug used in diverse types of cancer. However, muscle wasting is a common side effect of cisplatin chemotherapy. This study aimed to elucidate the effects of an ethanol extract of the root of Paeonia lactiflora Pall. (Radix Paeoniae, RP) on cisplatin-induced muscle wasting along with its molecular mechanism. MATERIAL AND METHODS: C57BL/6 mice were intraperitoneally injected with cisplatin and orally treated with RP. Megestrol acetate was used as a comparator drug. Skeletal muscle mass was measured as the weight of gastrocnemius and quadriceps muscles, and skeletal muscle function was measured by treadmill running time and grip strength. Skeletal muscle tissues were analyzed by RNAseq, western blotting, ELISA, and immunofluorescence microscopy. RESULTS: In mice treated with cisplatin, skeletal muscle mass and skeletal muscle function were significantly reduced. However, oral administration of RP significantly restored skeletal muscle mass and function in the cisplatin-treated mice. In the skeletal muscle tissues of the cisplatin-treated mice, RP downregulated NF-κB signaling and cytokine levels. RP also downregulated muscle-specific ubiquitin E3 ligases, resulting in the restoration of myosin heavy chain (MyHC) and myoblast determination protein (MyoD), which play crucial roles in muscle contraction and muscle differentiation, respectively. CONCLUSION: RP restored skeletal muscle function and mass in cisplatin-treated mice by restoring the muscle levels of MyHC and MyoD proteins via downregulation of muscle-specific ubiquitin E3 ligases as well as muscle NF-κB signaling and cytokine levels.