Fasting identifies SLIT2 as a novel driver of doxorubicin cardiotoxicity

Abstract

Intermittent fasting strategies, including alternate day fasting (ADF), may attenuate aging phenotypes and reduce cardiovascular risk in part by stimulating brown adipogenesis. However, in the setting of cardiotoxic doxorubicin (Dox) chemotherapy, we recently described a novel toxicity of sustained ADF, which stimulated cachexia and cardiac atrophy in mice. Presently, we tested the effect of fasting initiated after Dox chemotherapy and found that fasting caused a decline in lean body mass and left ventricular mass index, but increased body fat content, liver weight, and brown adipose tissue (BAT) weight index vs Dox-treated mice. Dox + ADF induced SLIT2, which regulates thermogenesis and metabolic function in BAT. Dox plus recombinant SLIT2 decreased left ventricular ejection fraction vs Dox alone. Plasma proteomics from patients showed that SLIT2 was the top protein associated with Dox cardiomyopathy vs other non-ischemic cardiomyopathy. This study suggests that SLIT2, an activator of brown adipogenesis, is a novel driver of Dox cardiotoxicity. This research was supported by NIH (R01HL155344, K08HL138262, P30DK056341, P30DK020579), Children's Discovery Institute of Washington University and St. Louis Children's Hospital (MC-FR-2020-919), and Longer Life Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.