@article{d63bc0400df447749d1ce5b52d0ae11b,
title = "Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity",
abstract = "Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate doxorubicin cardiotoxicity and stimulate nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. In this study, human heart tissue from patients with doxorubicin-induced heart failure demonstrated increased nuclear TFEB protein. In mice treated with doxorubicin, alternate-day fasting or viral TFEB transduction increased mortality and impaired cardiac function. Mice randomized to alternate-day fasting plus doxorubicin exhibited increased TFEB nuclear translocation in the myocardium. When combined with doxorubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, while recombinant GDF15 was sufficient to cause cardiac atrophy. Our studies identify that both sustained alternate-day fasting and a TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity.",
keywords = "TFEB, cardiotoxicity, doxorubicin, intermittent fasting",
author = "Mualla Ozcan and Zhen Guo and {Valenzuela Ripoll}, Carla and Ahmed Diab and Antonino Picataggi and David Rawnsley and Aynaz Lotfinaghsh and Carmen Bergom and Jeff Szymanski and Daniel Hwang and Aarti Asnani and Mikhail Kosiborod and Jie Zheng and Hayashi, {Robert J.} and Woodard, {Pamela K.} and Attila Kovacs and Margulies, {Kenneth B.} and Joel Schilling and Babak Razani and Abhinav Diwan and Ali Javaheri",
note = "Funding Information: A.J. was supported by K08HL138262 and 1R01HL155344 from the NHLBI; by the Children{\textquoteright}s Discovery Institute of Washington University ( MC-FR-2020-919 ) and St. Louis Children{\textquoteright}s Hospital , as well as the Diabetes Research Center at Washington University in St. Louis of the National Institutes of Health under award number P30DK020579 ; and by NIH grant P30DK056341 ( Nutrition Obesity Research Center ). Z.G. was supported by the American Heart Association Postdoctoral Fellowship ( 898679 ). A.A. was supported by K08HL145019 . A. Diwan was supported by grants from the Department of Veterans Affairs ( I01BX004235 ) and the National Institutes of Health ( HL107594 , HL143431 , and NS094692 ). C.B. was supported by R01HL147884 . We acknowledge support from the Advanced Imaging and Tissue Analysis Core of the Digestive Disease Research Core Center (DDRCC NIH P30DK052574 ) at Washington University School of Medicine. Funding for human cardiac MRI data was provided by the Children{\textquoteright}s Discovery Institute of Washington University and St. Louis Children{\textquoteright}s Hospital , grant number MC-II-2020-893 . This work was supported by the Hope Center Viral Vectors Core at Washington University School of Medicine. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = jun,
day = "6",
doi = "10.1016/j.cmet.2023.02.006",
language = "English",
volume = "35",
pages = "928--942.e4",
journal = "Cell metabolism",
issn = "1550-4131",
number = "6",
}