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Published on: April 10, 2019
Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis
Fatima Bianca A Dessouki1, Rakesh C Kukreja2, Dinender K Singla1
1Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Abstract:
Doxorubicin (Dox)-induced muscle toxicity (DIMT) is a common occurrence in cancer patients; however, the cause of its development and progression is not established. We tested whether inflammation-triggered cell death, "pyroptosis" plays a role in DIMT. We also examined the potential role of exosomes derived from embryonic stem cells (ES-Exos) in attenuating DIMT. C57BL/6J mice (10 ± 2 wks age) underwent the following treatments: Control (saline), Dox, Dox+ES-Exos, and Dox+MEF-Exos (mouse-embryonic fibroblast-derived exosomes, negative control). Our results demonstrated that Dox significantly reduced muscle function in mice, which was associated with a significant increase in NLRP3 inflammasome and initiation marker TLR4 as compared with controls. Pyroptosis activator, ASC, was significantly increased compared to controls with an upregulation of specific markers (caspase-1, IL-1β, and IL-18). Treatment with ES-Exos but not MEF-Exos showed a significant reduction in inflammasome and pyroptosis along with improved muscle function. Additionally, we detected a significant increase in pro-inflammatory cytokines (TNF-α and IL-6) and inflammatory M1 macrophages in Dox-treated animals. Treatment with ES-Exos decreased M1 macrophages and upregulated anti-inflammatory M2 macrophages. Furthermore, ES-Exos showed a significant reduction in muscular atrophy and fibrosis. In conclusion, these results suggest that DIMT is mediated through inflammation and pyroptosis, which is attenuated following treatment with ES-Exos.
Insights
Doxorubicin (Dox) causes muscle toxicity via pyroptosis. Embryonic stem cell-derived exosomes (ES-Exos) show promise in mitigating this inflammation-triggered cell death and improving muscle function.
Area of Science:
- Cellular Biology
- Toxicology
- Oncology
Background:
- Doxorubicin (Dox) is a widely used chemotherapy agent.
- Doxorubicin-induced muscle toxicity (DIMT) is a significant clinical challenge.
- The underlying mechanisms of DIMT, particularly the role of inflammation, are not fully understood.
Purpose of the Study:
- To investigate the role of pyroptosis, an inflammatory cell death pathway, in DIMT.
- To evaluate the therapeutic potential of exosomes derived from embryonic stem cells (ES-Exos) in attenuating DIMT.
Main Methods:
- C57BL/6J mice were treated with Dox, Dox+ES-Exos, or Dox+MEF-Exos (control exosomes).
- Muscle function, inflammasome activation (NLRP3, ASC, caspase-1), pyroptosis markers (IL-1β, IL-18), pro-inflammatory cytokines (TNF-α, IL-6), and macrophage polarization (M1/M2) were assessed.
- Muscular atrophy and fibrosis were also evaluated.
Main Results:
- Dox treatment significantly impaired muscle function and increased markers of pyroptosis and inflammasome activation.
- ES-Exos treatment, but not MEF-Exos, significantly reduced pyroptosis, inflammasome activation, and improved muscle function.
- ES-Exos decreased pro-inflammatory cytokines and M1 macrophages while increasing anti-inflammatory M2 macrophages, reducing muscle atrophy and fibrosis.
Conclusions:
- DIMT is significantly mediated by inflammation and pyroptosis.
- ES-Exos demonstrate a potent therapeutic effect in attenuating Dox-induced muscle toxicity.
- ES-Exos represent a promising strategy for managing chemotherapy-induced muscle damage.
