1. Academic Validation
  2. Irisin protects against doxorubicin-induced cardiotoxicity by improving AMPK-Nrf2 dependent mitochondrial fusion and strengthening endogenous anti-oxidant defense mechanisms

Irisin protects against doxorubicin-induced cardiotoxicity by improving AMPK-Nrf2 dependent mitochondrial fusion and strengthening endogenous anti-oxidant defense mechanisms

  • Toxicology. 2023 Jul 25;494:153597. doi: 10.1016/j.tox.2023.153597.
Caili Zhuo 1 Juanjuan Xin 1 Wenjing Huang 1 Die Zhang 1 Xin Yan 1 Ruli Li 1 He Li 1 Jie Lan 1 Lan Lin 1 Lingyu Li 1 Xuemei Wang 1 Linling Liu 2 Yingling Wang 1 Xinyue Li 1 Yan Mao 1 Hongying Chen 3 Sisi Wu 3 Xijing Yang 4 Wei Jiang 5
Affiliations

Affiliations

  • 1 Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 2 Department of Pharmacology, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China.
  • 3 Core Facilities, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 4 Animal Experiment Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 5 Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: wcumsjw@scu.edu.cn.
Abstract

Irisin, a new exercise-mediated myokine, plays an important role in cardiovascular diseases by regulating cell energy metabolism. The induction of mitochondrial dysfunction and oxidative stress are the crucial mechanisms involved in doxorubicin-induced cardiomyocyte damage and cardiac dysfunction, but the mitochondria-dependent protective mechanisms of irisin in DOX-impaired cardiomyocytes are poorly understood. In this study, we exposed mouse-FNDC5 (irisin-precursor)-knockout, FNDC5 transgenic mice and their WT littermates, as well as cultured neonatal rat cardiomyocytes to DOX at a dosage of 4 mg/kg (once a week for 4 weeks) in vivo and 2 μM in vitro, respectively, then investigated how irisin alleviated DOX-induced oxidative stress and myocardial injury. Irisin knockout worsened, while irisin overexpression attenuated DOX-induced mortality, body weight loss, myocardial atrophy, damage and oxidative stress, cardiac remodeling and dysfunction in mice. Exogenous irisin supplementation (20 nM) also relieved these DOX-induced damage in cardiomyocytes. Intriguingly, irisin activated AMPK-Nrf2 signaling axis, and then up-regulated the transcription and protein expression of the downstream target genes of Nrf2, including mitochondrial fusion-related genes (mitofusin 1/2 and Optic Atrophy Type 1) and endogenous anti-oxidant genes, to promote mitochondrial fusion, improve mitochondrial dynamics and mitochondrial function, and reduced oxidative stress damage in DOX-induced cardiomyocytes. These results suggest that irisin protects the hearts from DOX-induced cardiotoxicity by improving mitochondrial dynamics and strengthening the endogenous anti-oxidant system through an AMPK-Nrf2 axis dependent manner, thus reducing DOX-induced oxidative stress injury in cardiomyocytes.

Keywords

Cardiotoxicity; Doxorubicin; Endogenous anti-oxidants; Irisin; Mitochondrial dynamics; Oxidative stress.

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