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Updated: Jul 19, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
MST1 mediates doxorubicin-induced cardiomyopathy by SIRT3 downregulation
Leonardo Schirone1, Daniele Vecchio1, Valentina Valenti2
1Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
Abstract:
Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.
Insights
Doxorubicin (DOX) chemotherapy can cause heart failure by activating the MST1 pathway, which lowers protective SIRT3 levels. Inhibiting MST1 protects the heart from DOX damage, offering a potential therapeutic strategy for cancer patients.
Area of Science:
- Cardiovascular Biology
- Cancer Therapeutics
- Molecular Medicine
Background:
- Doxorubicin (DOX) is a vital chemotherapy agent but causes significant cardiotoxicity, leading to heart failure.
- The precise molecular mechanisms driving DOX-induced cardiomyopathy remain incompletely understood.
- The Hippo pathway kinase MST1 is implicated in cellular stress responses, but its role in DOX cardiotoxicity is unclear.
Purpose of the Study:
- To investigate the contribution of the serine/threonine kinase MST1 to doxorubicin-induced myocardial injury.
- To elucidate the molecular pathway linking MST1 activation to DOX cardiotoxicity.
- To evaluate MST1 inhibition as a potential strategy to prevent DOX-induced heart damage.
Main Methods:
- Utilized C57BL/6J wild-type (WT) mice and cardiomyocyte-specific dominant-negative MST1 (DN-MST1) transgenic mice.
- Administered weekly doxorubicin injections (cumulative dose 18 mg/kg) followed by echocardiographic, histological, and biochemical analyses.
- Assessed MST1 signaling, mitochondrial function, SIRT3 levels, and cardiomyocyte injury in vitro and in vivo, including experiments with MST1 inhibitor XMU-MP-1 and SIRT3 inhibition.
Main Results:
- Doxorubicin treatment significantly activated MST1 signaling in cardiomyocytes, both in vitro and in vivo.
- WT mice receiving DOX developed cardiac dysfunction and mitochondrial abnormalities, which were prevented in DN-MST1 mice and mice treated with XMU-MP-1.
- DOX induced downregulation of mitochondrial deacetylase SIRT3 in WT mice, an effect reversed by MST1 inhibition; pharmacological inhibition of SIRT3 abolished the protective effects of MST1 inhibition.
- Elevated MST1 and reduced SIRT3 levels were observed in human myocardial tissue from DOX-treated cancer patients.
Conclusions:
- MST1 activation is a key mediator of doxorubicin-induced cardiotoxicity.
- MST1 contributes to DOX-induced myocardial injury through the downregulation of the mitochondrial protective factor SIRT3.
- Inhibition of MST1 signaling represents a promising therapeutic approach to mitigate doxorubicin cardiotoxicity in cancer patients.
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