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Updated: Jul 3, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
A mouse model for juvenile doxorubicin-induced cardiac dysfunction
Wuqiang Zhu1, Weinian Shou, R Mark Payne
1Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 26202, USA.
Abstract:
Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases.
Insights
This study developed a juvenile mouse model for chronic doxorubicin (DOX) cardiotoxicity. Juvenile mice showed impaired cardiac function and growth, with distinct mechanisms of dysfunction during treatment and recovery.
Area of Science:
- Cardiology
- Pharmacology
- Toxicology
Background:
- Doxorubicin (DOX) is a vital chemotherapy drug but causes dose-dependent cardiotoxicity, particularly in children.
- Understanding the molecular mechanisms of DOX-induced cardiotoxicity is crucial for developing preventative strategies.
- Existing mouse models often use acute administration in adult animals, limiting insights into chronic effects.
Purpose of the Study:
- To establish and characterize a juvenile mouse model for chronic doxorubicin (DOX)-induced cardiotoxicity.
- To investigate the cardiac functional and structural changes during DOX treatment and subsequent recovery in young animals.
- To explore the underlying mechanisms of cardiac dysfunction in different phases of the model.
Main Methods:
- Juvenile mice (2 weeks old) received chronic doxorubicin (DOX) treatment over 5 weeks (25 mg/kg cumulative dose).
- Cardiac function was assessed, and cardiac tissues were analyzed for cardiomyocyte apoptosis, atrophy, and fibrosis.
- Animals underwent a 13-week recovery period post-DOX to evaluate long-term effects.
Main Results:
- Chronic DOX treatment in juvenile mice led to decreased cardiac systolic function, significant cardiac atrophy, and reduced growth velocity.
- Despite recovery of cardiac size, systolic function remained impaired after DOX withdrawal.
- Increased cardiomyocyte apoptosis and myocardial fibrosis were observed during the recovery phase.
Conclusions:
- This juvenile mouse model effectively recapitulates chronic doxorubicin (DOX)-induced cardiotoxicity and cardiac dysfunction.
- Cardiac dysfunction during DOX treatment and recovery phases involves distinct underlying mechanisms.
- The findings highlight the long-term cardiac risks associated with DOX therapy in young individuals.
