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Article Abstract
Doxorubicin (DOX) is widely used in cancer therapy, but its cardiac toxicity remains a significant challenge. Sex plays a role in DOX-induced cardiotoxicity, with females exhibiting less sensitivity. However, the precise molecular mechanisms underlying this difference are not fully understood. This study investigated the impact of low-dose and short-term DOX treatment on mitochondrial activity, reactive oxygen species (ROS) and calcium signaling in cardiomyocytes isolated from adult male and female C57BL/6 mice. It was found that 3 μM DOX treatment for 15 min specifically increase the fluorescence of MitoTracker Red CMXRos in male cardiomyocytes rather than female, without affecting cell viability and ROS generation. DOX also induced more shrunk male cells, which were more sensitive to DOX-induced shorten of sarcomere length. In terms of calcium signaling, more male cells exhibited spontaneous calcium oscillations following DOX treatment. In electrical field stimulation, male cells displayed smaller calcium transient amplitude, lower SR calcium content, less efficient calcium re-uptake than female, and exhibited weaker response to DOX. These findings suggest that female cardiomyocytes manage mitochondrial activity and calcium signaling more effectively in antagonizing DOX treatment, explaining the sex differences in cardiotoxicity. This study explores sex differences in the early phase of DOX-induced cardiac function from the perspective of single-cell and cellular signaling, highlighting the importance of considering sex differences in designing cancer therapeutic strategies.
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| http://dx.doi.org/10.1016/j.bbrc.2025.152328 | DOI Listing |
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