6‐Shogaol Attenuates Doxorubicin‐Induced Cardiac and Skeletal Muscle Atrophy by Inhibiting <scp>E3</scp> Ubiquitin Ligases and Necroptosis

Doxorubicin (DOX) is an effective anticancer agent, but it not only induces dose-dependent cardiotoxicity but also causes severe cardiac and skeletal muscle atrophy. Recent studies have indicated that cardiac atrophy may play an important role in DOX-induced cardiotoxicity. However, the mechanisms responsible for DOX-induced cardiac and skeletal muscle atrophy remain unclear. 6-Shogaol (6-SH) is a bioactive component from ginger, which exhibits various bioactive effects and can alleviate cisplatin-induced cachexia. In this work, we systematically assessed the effects of DOX and/or 6-SH on heart and skeletal muscle, as well as the underlying mechanisms. C57BL/6 mice were treated with DOX (5 mg/kg/3d, 4 doses, intraperitoneal) and given high or low doses of 6-SH (10/2.5 mg/kg, qd, intraperitoneal) for 14 days. Body weight, skeletal muscle mass, heart mass, grip strength, food intake and cardiac function were significantly reduced in DOX-treated mice, with these impairments notably ameliorated by 6-SH. Unexpectedly, 6-SH synergistically enhanced the antitumor efficacy of DOX. The DOX-induced significant decline in mitochondrial levels and slow-to-fast fiber type shift in skeletal muscle were notably attenuated by 6-SH treatment. Meanwhile, 6-SH exerted a protective effect against DOX-induced increases in cardiac oxidative stress, cardiac injury markers and inflammatory cytokines. DOX significantly upregulated the E3 ubiquitin ligases Atrogin1 and MuRF1 and downregulated MyoD and MyoG in the heart and skeletal muscle. Furthermore, DOX activated necroptosis, as evidenced by increased phosphorylation of receptor-interacting protein kinase (RIPK) 1, RIPK3, and mixed-lineage kinase domain-like (MLKL). 6-SH negatively regulated E3 ubiquitin ligases and necroptosis, while upregulating myogenic regulatory factors. In conclusion, 6-SH attenuated DOX-induced cardiac atrophy, skeletal muscle atrophy and cardiotoxicity by inhibiting E3 ubiquitin ligases and necroptosis.