美国华盛顿大学医学院Ali Javaheri研究团队揭示了持续隔天禁食增强阿霉素心脏毒性。相关论文于2023年3月2日发表在《细胞—代谢》杂志上。
在这项研究中，来自阿霉素诱导的心力衰竭患者的人类心脏组织显示出核转录因子EB（TFEB）蛋白的增加。在用阿霉素治疗的小鼠中，隔日禁食或病毒TFEB转导增加了死亡率和心脏功能受损。随机分配到隔日禁食加阿霉素的小鼠在心肌中表现出增加的TFEB核易位。当与阿霉素联合使用时，心肌细胞特异性TFEB过表达引起心脏重塑，而全身TFEB过表达增加生长分化因子15（GDF15）并导致心力衰竭和死亡。
心肌细胞TFEB敲除减弱了阿霉素的心脏毒性，而重组GDF15足以引起心脏萎缩。他们的研究发现，持续的隔日禁食和TFEB/GDF15途径都会加剧阿霉素的心脏毒性。
据悉，正在对接受化疗的患者进行积极的临床研究。先前的小鼠研究表明，隔日禁食可能会减弱阿霉素的心脏毒性并刺激TFEB的核易位，TFEB是自噬和溶酶体生物发生的主要调节因子。
附：英文原文
Title: Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity
Author: Mualla Ozcan, Zhen Guo, Carla Valenzuela Ripoll, Ahmed Diab, Antonino Picataggi, David Rawnsley, Aynaz Lotfinaghsh, Carmen Bergom, Jeff Szymanski, Daniel Hwang, Aarti Asnani, Mikhail Kosiborod, Jie Zheng, Robert J. Hayashi, Pamela K. Woodard, Attila Kovacs, Kenneth B. Margulies, Joel Schilling, Babak Razani, Abhinav Diwan, Ali Javaheri
Issue&Volume: 2023-03-02
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.
DOI: 10.1016/j.cmet.2023.02.006
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00042-6
Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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本期文章：《细胞—代谢》：Online/在线发表
