Funded in part by Amgen, Eli Lilly and Company, AstraZeneca, Sanofi, Bayer HealthCare, Vifor Pharma, Janssen Pharmaceuticals
Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity
Ozcan M, Guo Z, Valenzuela Ripoll C, Diab A, Picataggi A, Rawnsley D, Lotfinaghsh A, Bergom C, Szymanski J, Hwang D, Asnani A, Kosiborod M, Zheng J, Hayashi RJ, Woodard PK, Kovacs A, Margulies KB, Schilling J, Razani B, Diwan A, Javaheri A
Cell metabolism · 79 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Randomized controlled trial (indexed by PubMed)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Industry funded
- Government
- U.S. Department of Veterans Affairs
- Nonprofit
- American Heart Association
- Company
- Amgen
- Company
- Eli Lilly and Company
- Company
- AstraZeneca
- Company
- Sanofi
- University or hospital
- Washington University in St. Louis
- University or hospital
- Children's Discovery Institute
- Nonprofit
- Hope Center for Neurological Disorders
- University or hospital
- St. Louis Children's Hospital
- Company
- Bayer HealthCare
- Company
- Vifor Pharma
- Government
- National Institutes of Health
- Government
- National Heart, Lung, and Blood Institute
- Government
- National Institute of Diabetes and Digestive and Kidney Diseases
- Government
- National Institute of Neurological Disorders and Stroke
- Company
- Janssen Pharmaceuticals
- Government
- NIH
- Government
- NHLBI NIH HHS
- Government
- BLRD VA
- Government
- NIDDK NIH HHS
- Government
- NINDS NIH HHS
- University or hospital
- St. Louis Children's Hospital
- Government
- NHLBI
- Government
- NIH HHS
- University or hospital
- Washington University in Saint Louis Children's Discovery Institute
- Grants
- National Heart, Lung, and Blood Institute (K08 HL163469); U.S. Department of Veterans Affairs (HL107594); National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK056341); National Heart, Lung, and Blood Institute (R01HL159461); American Heart Association (898679); U.S. Department of Veterans Affairs (I01BX004235); U.S. Department of Veterans Affairs (I01BX005981); National Institutes of Health (1s10od028597-01); National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020579); U.S. Department of Veterans Affairs (R01HL147884); National Heart, Lung, and Blood Institute (K08 HL138262); National Heart, Lung, and Blood Institute (R01HL147884); National Heart, Lung, and Blood Institute (HL143431); U.S. Department of Veterans Affairs (MC-II-2020-893); National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK052574-); National Heart, Lung, and Blood Institute (R01 HL155344); National Institute of Neurological Disorders and Stroke (R01 NS094692); U.S. Department of Veterans Affairs (I01 BX003415); U.S. Department of Veterans Affairs (HL143431); Children's Discovery Institute (MC-FR-2020-919); U.S. Department of Veterans Affairs (P30DK052574); U.S. Department of Veterans Affairs (NS094692); National Heart, Lung, and Blood Institute (R01 HL125838); National Heart, Lung, and Blood Institute (R01 HL143431); Washington University in St. Louis (P30 DK052574); National Heart, Lung, and Blood Institute (1R01HL155344); National Heart, Lung, and Blood Institute (R01 HL107594); National Heart, Lung, and Blood Institute (K08HL145019); National Institutes of Health (P30-DK020579); National Institutes of Health (K08-HL145019); National Institutes of Health (P30DK056341); National Institutes of Health (P30 DK052574); National Institutes of Health (HL107594); National Institutes of Health (R01HL147884); National Institutes of Health (NS094692); National Heart, Lung, and Blood Institute (HL107594); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK131188)
Based on 26 listed funder(s).
Publication
- Published
- 2023-03-02 · Cell Metab · vol. 35 · issue 6 · pp. 928–942.e4
- Publisher
- Cell Press
- Cited
- 101 citations · more than 100% of similar papers · 18.5× the field average
- Impact
- Top 10% most cited in its field
- References
- 41 works
- Access
- Open access (hybrid journal) · CC-BY-NC-ND
- Research areas
- GDF15 and Related Biomarkers · Nutrition and Health in Aging · Cancer-related cognitive impairment studies
- Keywords
- TFEB, Cardiotoxicity, Doxorubicin, Autophagy, Heart failure, Medicine, Internal medicine, Endocrinology, Cancer research, Biology, Chemotherapy, Apoptosis, Biochemistry
- MeSH
- lysosomes, myocytes, cardiac, animals, humans, mice, doxorubicin, fasting, autophagy, basic helix-loop-helix leucine zipper transcription factors, heart failure, cardiotoxicity
21 authors
From US
- Mualla ÖzcanWashington University in St. Louis
- Zhen GuoWashington University in St. Louis
- Carla Valenzuela RipollWashington University in St. Louis
- Ahmed DiabWashington University in St. Louis
- Antonino PicataggiWashington University in St. Louis
- David R. RawnsleyWashington University in St. Louis
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC-ND).
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