Doxorubicin (Dox) has been one of the most effective chemotherapeutic drugs against a wide range of cancers. The use of Dox is restricted due to severe clinical side effects including Dox-induced skeletal muscle toxicity (DIMT). The exact molecular mechanisms in the progression and development of DIMT have not been established. We investigated the roles of inflammatory cell deaths pyroptosis and necroptosis in DIMT. Additionally, we explored the therapeutic potential of embryonic stem cell-derived exosomes (ES-Exos) in diminishing DIMT. Mice were used to develop DIMT and pre-diabetic animal models of muscle toxicity. Mice were subjected to muscle function and glucose tolerance testing. Soleus and gastrocnemius tissues were collected for protein expression assays including immunohistochemistry, western blot, ELISA, and RT-PCR to determine pyroptosis, inflammasome formation, M1 and M2 macrophages, necroptosis and necroinflammation levels. Histology staining was performed to determine atrophy and fibrosis. Muscle strength of mice were significantly (p < 0.05) diminished for Dox vs. controls whereas ES-Exos significantly (p < 0.05) mitigated this muscle dysfunction by enhancing muscle strength. In parallel, our results showed a significant (p < 0.05) increase in muscle atrophy, fibrosis, inflammasome formation leading to inflammation-induced cell death pyroptosis, necroinflammation, and pro-inflammatory M1 macrophage markers for Dox compared with controls. Treatment with ES-Exos significantly (p < 0.05) reduced atrophy, fibrosis, inflammation, inflammatory cytokines, and pyroptosis. Noticeably, ES-Exos treatment significantly enhanced anti-inflammatory M2 macrophages in the muscle. Necroptosis and necroinflammation markers, along with atrophy and fibrosis, were significantly (p < 0.05) increased in the combined model of Dox and pre-diabetes compared with pre-diabetes alone, suggesting that Dox administration in pre-diabetic conditions have enhanced detrimental effects. Overall, this novel study establishes the mechanistic roles of inflammatory cell deaths pyroptosis and necroptosis, inflammatory cytokines, and inflammatory macrophages in skeletal muscle toxicity. Moreover, we established the protective effects of Exos in muscle toxicity models involving Dox.
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Master of Science (M.S.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Masters Thesis (Campus-only Access)
Dessouki, Fatima Bianca, "Doxorubicin-Induced Differential Patterns of Cell Death in the Skeletal Muscle" (2021). Electronic Theses and Dissertations, 2020-. 494.