Both BMH-21 and doxorubicin reduced markers of ribosome biogenesis in cardiac tissue, suggesting impaired protein synthesis capacity contributes to chemotherapy-induced cardiotoxicity.
Do doxorubicin and BMH-21 induce cardiotoxicity and inhibit ribosome biogenesis in female C57Bl/6J mice?
Both doxorubicin and the novel agent BMH-21 reduce markers of ribosome biogenesis in cardiac tissue, suggesting this pathway as a potential mechanism for chemotherapy-induced cardiotoxicity and muscle wasting.
Chemotherapy drugs often accumulate in healthy tissues, resulting in off-target effects and lasting sequelae. Particularly to the heart, chemotherapy drugs can lead to cardiotoxicity and potentially heart failure. While some side effects of Doxorubicin, a widely used chemotherapy drug, in the cardiac muscle are known, the effects of BMH-21, a novel chemotherapy drug which targets ribosome biogenesis, are much less understood. Given that chemotherapy drugs often target tumor cells via ribosome biogenesis, we hypothesize that Doxorubicin and BMH-21 cause cardiac muscle wasting via (at least partially) their inhibitory effect on ribosome biogenesis. Elucidating the role of chemotherapy on cardiac muscle will help determine the cellular mechanisms of cardiotoxicity and lead to better treatment options to mitigate cardiac muscle wasting in cancer patients in the future. Female C57Bl/6J mice were assigned to two treatment cohorts: BMH-21 (25 mg/kg; 5 days on, 2 days off for 2 weeks) or doxorubicin (6 mg/kg every 5 days for 2 weeks), each with vehicle controls (n=10 per cohort; 3 controls and 7 experimental). Body weight, food intake, and grip strength were measured longitudinally. 5-Ethynyl Uridine (5-EU) was injected 5 hours prior to tissue collection to label nascent RNA. Total RNA was extracted from cardiac tissue, followed by 5-EU pulldown, complementary DNA (cDNA) synthesis, and quantitative real-time polymerase chain reaction (RT-qPCR) to assess markers of ribosome biogenesis, including 45S pre-ribosomal RNA (pre-rRNA) and 28S ribosomal RNA (rRNA). Statistical analyses included one-way and two-way analysis of variance (ANOVA). BMH-21 treatment did not significantly alter body weight or food intake but led to a significant reduction in grip strength and a non-significant trend toward lower heart mass. Doxorubicin treatment significantly reduced body weight over time and resulted in significantly smaller normalized heart mass compared to controls. Both treatments resulted in decreased 5-EU-labeled rRNA and pre-rRNA levels, indicating reduced ribosome biogenesis. Markers of ribophagy (Nufip1) were not significantly altered. Doxorubicin induced clear cardiotoxicity, including cardiac atrophy and weight loss. BMH-21 produced early signs of cardiac and neuromuscular impairment despite preserved body weight. Both drugs reduced markers of ribosome biogenesis in cardiac tissue, suggesting impaired protein synthesis capacity. These findings support the hypothesis that doxorubicin and BMH-21 induce cardiotoxicity, at least in part, through inhibition of ribosome biogenesis. Reduced ribosome synthesis may contribute to impaired cardiac muscle maintenance and function. These results highlight ribosome biogenesis as a potential mechanistic target for understanding and mitigating chemotherapy-induced cardiac muscle wasting. This project was funded by the American Heart Association’s Supporting Undergraduate Research Experiences (SURE) Program (Grant ID 25SURE1512018) and by Oakland University’s Undergraduate Provost Award to GAF, and by the National Institutes of Health (Grant ID 1R15AR083675-01) to VCF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Ferraz et al. (2026) studied Chemotherapy-induced cardiotoxicity (n=20). BMH-21 and Doxorubicin vs. Vehicle controls was evaluated on Markers of ribosome biogenesis (45S pre-rRNA and 28S rRNA), body weight, food intake, grip strength, and heart mass. Both BMH-21 and doxorubicin reduced markers of ribosome biogenesis in cardiac tissue, suggesting impaired protein synthesis capacity contributes to chemotherapy-induced cardiotoxicity.