Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

被引：47

作者：

Ozcan, Mualla ^{[1
]}

Guo, Zhen ^{[1
]}

Ripoll, Carla Valenzuela ^{[1
]}

Diab, Ahmed ^{[1
]}

Picataggi, Antonino ^{[1
]}

Rawnsley, David ^{[1
]}

Lotfinaghsh, Aynaz ^{[1
]}

Bergom, Carmen ^{[1
]}

Szymanski, Jeff ^{[1
]}

Hwang, Daniel ^{[1
]}

Asnani, Aarti ^{[2
]}

Kosiborod, Mikhail ^{[3
]}

Zheng, Jie ^{[1
]}

Hayashi, Robert J. ^{[1
]}

Woodard, Pamela K. ^{[1
]}

Kovacs, Attila ^{[1
]}

Margulies, Kenneth B. ^{[4
]}

Schilling, Joel ^{[1
]}

Razani, Babak ^{[1
,5
]}

Diwan, Abhinav ^{[1
,5
]}

Javaheri, Ali ^{[1
]}

机构：

[1] Washington Univ, Sch Med, St Louis, MO 63110 USA

[2] Beth Israel & Harvard Med Sch, Boston, MA USA

[3] St Lukes Kansas City, Kansas City, MO USA

[4] Univ Penn, Perelman Sch Med, Philadelphia, PA USA

[5] John Cochran Vet Affairs Med Ctr, St Louis, MO USA

来源：

CELL METABOLISM | 2023年 / 35卷 / 06期

基金：

美国国家卫生研究院;

关键词：

EXPRESSION; DIET; REGENERATION; MYOCARDIUM; METABOLISM; AXIS;

D O I：

10.1016/j.cmet.2023.02.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 trans-duction 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 doxo-rubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Car-diomyocyte 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.

引用

页码：928 / +

页数：20

共 40 条

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