2. Academic Validation
  3. 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.
PMID: 37499777 DOI: 10.1016/j.tox.2023.153597
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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