FGF21–Sirtuin 3 Axis Confers the Protective Effects of Exercise Against Diabetic Cardiomyopathy by Governing Mitochondrial Integrity

Leigang Jin, Leiluo Geng, Lei Ying, Lingling Shu, Kevin Ye, Ranyao Yang, Yan Liu, Yao Wang, Yin Cai, Xue Jiang, Qin Wang, Xingqun Yan, Boya Liao, Jie Liu, Fuyu Duan, Gray Sweeney, Connie Wai Hong Woo, Yu Wang, Zhengyuan Xia, Qizhou Lian*Aimin Xu*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

53 Citations (Scopus)

Abstract

Background: Exercise is an effective nonpharmacological strategy to alleviate diabetic cardiomyopathy (DCM) through poorly defined mechanisms. FGF21 (fibroblast growth factor 21), a peptide hormone with pleiotropic benefits on cardiometabolic homeostasis, has been identified as an exercise responsive factor. This study aims to investigate whether FGF21 signaling mediates the benefits of exercise on DCM, and if so, to elucidate the underlying mechanisms.

Methods: The global or hepatocyte-specific FGF21 knockout mice, cardiomyocyte-selective β-klotho (the obligatory co-receptor for FGF21) knockout mice, and their wild-type littermates were subjected to high-fat diet feeding and injection of streptozotocin to induce DCM, followed by a 6-week exercise intervention and assessment of cardiac functions. Cardiac mitochondrial structure and function were assessed by electron microscopy, enzymatic assays, and measurements of fatty acid oxidation and ATP production. Human induced pluripotent stem cell-derived cardiomyocytes were used to investigate the receptor and postreceptor signaling pathways conferring the protective effects of FGF21 against toxic lipids-induced mitochondrial dysfunction.

Results: Treadmill exercise markedly induced cardiac expression of β-klotho and significantly attenuated diabetes-induced cardiac dysfunction in wild-type mice, accompanied by reduced mitochondrial damage and increased activities of mitochondrial enzymes in hearts. However, such cardioprotective benefits of exercise were largely abrogated in mice with global or hepatocyte-selective ablation of FGF21, or cardiomyocyte-specific deletion of β-klotho. Mechanistically, exercise enhanced the cardiac actions of FGF21 to induce the expression of the mitochondrial deacetylase SIRT3 by AMPK-evoked phosphorylation of FOXO3, thereby reversing diabetes-induced hyperacetylation and functional impairments of a cluster of mitochondrial enzymes. FGF21 prevented toxic lipids-induced mitochondrial dysfunction and oxidative stress by induction of the AMPK/FOXO3/SIRT3 signaling axis in human induced pluripotent stem cell-derived cardiomyocytes. Adeno-associated virus-mediated restoration of cardiac SIRT3 expression was sufficient to restore the responsiveness of diabetic FGF21 knockout mice to exercise in amelioration of mitochondrial dysfunction and DCM.

Conclusions: The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM.
Original languageEnglish
Pages (from-to)1537-1557
Number of pages21
JournalCirculation
Volume146
Issue number20
DOIs
Publication statusPublished - 15 Nov 2022

User-Defined Keywords

  • SIRT3
  • exercise
  • mitochondrial dysfunction
  • diabetic cardiomyopathy
  • FGF21

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