Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.

The 2nd Affiliated Hospital Department of Clinical Pharmacy Hengyang Medical School University of South China Hengyang Hunan China

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Ali S, Garcia JM. Sarcopenia, cachexia and aging: diagnosis, mechanisms and therapeutic options - a mini-review. Gerontology. 2014;60:294–305. doi: 10.1159/000356760. PubMed DOI PMC

Amjad MT, Chidharla A, Kasi A. StatPearls [Internet] Treasure Island (FL): StatPearls Publishing; 2024. Jan, Cancer Chemotherapy. PubMed

Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–378. doi: 10.1016/j.ejphar.2014.07.025. PubMed DOI PMC

Tchounwou PB, Dasari S, Noubissi FK, Ray P, Kumar S. Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy. J Exp Pharmacol. 2021;13:303–328. doi: 10.2147/JEP.S267383. PubMed DOI PMC

Wu YJ, Muldoon LL, Neuwelt EA. The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther. 2005;312:424–431. doi: 10.1124/jpet.104.075119. PubMed DOI

Florea AM, Busselberg D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel) 2011;3:1351–1371. doi: 10.3390/cancers3011351. PubMed DOI PMC

Jing N, Li X. Dihydromyricetin Attenuates Inflammation through TLR4/NF-kappaB Pathway. Open Med (Wars) 2019;14:719–725. doi: 10.1515/med-2019-0083. PubMed DOI PMC

Hou L, Jiang F, Huang B, Zheng W, Jiang Y, Cai G, Liu D, et al. Dihydromyricetin resists inflammation-induced muscle atrophy via ryanodine receptor-CaMKK-AMPK signal pathway. J Cell Mol Med. 2021;25:9953–9971. doi: 10.1111/jcmm.16810. PubMed DOI PMC

Shi L, Zhang T, Zhou Y, Zeng X, Ran L, Zhang Q, Zhu J, Mi M. Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1alpha-Sirt3 signaling pathway. Endocrine. 2015;50:378–389. doi: 10.1007/s12020-015-0599-5. PubMed DOI

Xu Z, Zhang M, Wang W, Zhou S, Yu M, Qiu X, Jiang S, et al. Dihydromyricetin attenuates cisplatin-induced acute kidney injury by reducing oxidative stress, inflammation and ferroptosis. Toxicol Appl Pharmacol. 2023;473:116595. doi: 10.1016/j.taap.2023.116595. PubMed DOI

Zhou Q, Gu Y, Lang H, Wang X, Chen K, Gong X, Zhou M, et al. Dihydromyricetin prevents obesity-induced slow-twitch-fiber reduction partially via FLCN/FNIP1/AMPK pathway. Biochim Biophys Acta Mol Basis Dis. 2017;1863:1282–1291. doi: 10.1016/j.bbadis.2017.03.019. PubMed DOI

Hernandez-Rodriguez J, Segarra M, Vilardell C, Sanchez M, Garcia-Martinez A, Esteban MJ, Queralt C, et al. Tissue production of pro-inflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology (Oxford) 2004;43:294–301. doi: 10.1093/rheumatology/keh058. PubMed DOI

Matouk AI, Awad EM, El-Tahawy NFG, El-Sheikh AAK, Anter A. Dihydromyricetin Modulates Nrf2 and NF-kappaB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity. Pharmaceuticals (Basel) 2023;16:481. doi: 10.3390/ph16040481. PubMed DOI PMC

Sakai H, Ikeno Y, Tsukimura Y, Inomata M, Suzuki Y, Kon R, Ikarashi N, et al. Upregulation of ubiquitinated proteins and their degradation pathway in muscle atrophy induced by cisplatin in mice. Toxicol Appl Pharmacol. 2020;403:115165. doi: 10.1016/j.taap.2020.115165. PubMed DOI

Wu CT, Liao JM, Ko JL, Lee YL, Chang HY, Wu CH, Ou CC. D-Methionine Ameliorates Cisplatin-Induced Muscle Atrophy via Inhibition of Muscle Degradation Pathway. Integr Cancer Ther. 2019;18:1534735419828832. doi: 10.1177/1534735419828832. PubMed DOI PMC

de Palma L, Marinelli M, Pavan M, Orazi A. Ubiquitin ligases MuRF1 and MAFbx in human skeletal muscle atrophy. Joint Bone Spine. 2008;75:53–57. doi: 10.1016/j.jbspin.2007.04.019. PubMed DOI

Murton AJ. Muscle atrophy; more than one string to MuRF1’s bow? J Physiol. 2011;589:4635. doi: 10.1113/jphysiol.2011.218552. PubMed DOI PMC

Bodine SC, Baehr LM. Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1. Am J Physiol Endocrinol Metab. 2014;307:E469–E484. doi: 10.1152/ajpendo.00204.2014. PubMed DOI PMC

Liu X, Xu M, Yu Y, Chen Y, Weng X, Zhu L. PD-1 Alleviates Cisplatin-Induced Muscle Atrophy by Regulating Inflammation and Oxidative Stress. Antioxidants (Basel) 2022;11:1839. doi: 10.3390/antiox11091839. PubMed DOI PMC

Conte E, Bresciani E, Rizzi L, Cappellari O, De Luca A, Torsello A, Liantonio A. Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies. Int J Mol Sci. 2020;21:1242. doi: 10.3390/ijms21041242. PubMed DOI PMC

Du B, Wang S, Zhu S, Li Y, Huang D, Chen S. Antioxidant Activities of Dihydromyricetin Derivatives with Different Acyl Donor Chain Lengths Synthetized by Lipozyme TL IM. Foods. 2023;12:1986. doi: 10.3390/foods12101986. PubMed DOI PMC

Wei C, Chen X, Chen D, Yu B, Zheng P, He J, Chen H, et al. Dihydromyricetin Enhances Intestinal Antioxidant Capacity of Growing-Finishing Pigs by Activating ERK/Nrf2/HO-1 Signaling Pathway. Antioxidants (Basel) 2022;11:704. doi: 10.3390/antiox11040704. PubMed DOI PMC

Tian Y, Lu J, Hao X, Li H, Zhang G, Liu X, Li X, et al. FTH1 Inhibits Ferroptosis Through Ferritinophagy in the 6-OHDA Model of Parkinson’s Disease. Neurotherapeutics. 2020;17:1796–1812. doi: 10.1007/s13311-020-00929-z. PubMed DOI PMC

Chen J, Ou Z, Gao T, Yang Y, Shu A, Xu H, Chen Y, Lv Z. Ginkgolide B alleviates oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination to improve diabetic nephropathy. Biomed Pharmacother. 2022;156:113953. doi: 10.1016/j.biopha.2022.113953. PubMed DOI

Lin Q, Li S, Jin H, Cai H, Zhu X, Yang Y, Wu J, et al. Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis. Int J Biol Sci. 2023;19:1192–1210. doi: 10.7150/ijbs.80775. PubMed DOI PMC

Liu Q, Wang K. The induction of ferroptosis by impairing STAT3/Nrf2/GPx4 signaling enhances the sensitivity of osteosarcoma cells to cisplatin. Cell Biol Int. 2019;43:1245–1256. doi: 10.1002/cbin.11121. PubMed DOI

Kim DH, Choi HI, Park JS, Kim CS, Bae EH, Ma SK, Kim SW. Farnesoid X receptor protects against cisplatin-induced acute kidney injury by regulating the transcription of ferroptosis-related genes. Redox Biol. 2022;54:102382. doi: 10.1016/j.redox.2022.102382. PubMed DOI PMC

Wu Y, Pi D, Zhou S, Wang W, Ye H, Yi Z, Chen Y, Ouyang M. Yiqi Chutan Formula Reverses Cisplatin-Induced Apoptosis and Ferroptosis of Skeletal Muscle by Alleviating Oxidative Stress. Integr Cancer Ther. 2023;22:15347354231172117. doi: 10.1177/15347354231172117. PubMed DOI PMC

Xie J, Zhang T, Li P, Wang D, Liu T, Xu S. Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis. Drug Des Devel Ther. 2022;16:3071–3085. doi: 10.2147/DDDT.S378786. PubMed DOI PMC