Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

Area of Science:

• Cardiology
• Oncology
• Molecular Biology

Background:

• Fasting is being studied in chemotherapy patients.
• Alternate-day fasting may reduce doxorubicin cardiotoxicity and increase TFEB.
• Human heart tissue from doxorubicin-induced heart failure shows increased nuclear TFEB.

Purpose of the Study:

• To investigate the impact of alternate-day fasting and TFEB on doxorubicin cardiotoxicity.
• To explore the role of the TFEB/GDF15 pathway in chemotherapy-induced heart damage.

Main Methods:

• Murine models treated with doxorubicin, alternate-day fasting, and/or TFEB manipulation.
• Analysis of human heart tissue for TFEB levels.
• Cardiomyocyte-specific TFEB overexpression and knockout studies.
• Assessment of cardiac function, remodeling, mortality, and GDF15 levels.

Main Results:

• Alternate-day fasting and TFEB transduction increased mortality and impaired cardiac function in doxorubicin-treated mice.
• TFEB nuclear translocation was elevated in the myocardium of mice on alternate-day fasting plus doxorubicin.
• TFEB overexpression in cardiomyocytes caused cardiac remodeling; systemic TFEB overexpression led to heart failure and death via GDF15.
• Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, and recombinant GDF15 induced cardiac atrophy.

Conclusions:

• Sustained alternate-day fasting and the TFEB/GDF15 pathway significantly exacerbate doxorubicin cardiotoxicity.
• Targeting TFEB or GDF15 may offer novel therapeutic strategies for mitigating chemotherapy-induced heart damage.