Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction

Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigate...

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Autores principales:	Yixuan Ma, Yixin Kuang, Wenyan Bo, Qiaoqin Liang, Wenfei Zhu, Mengxin Cai, Zhenjun Tian
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	exercise training myocardial infarction cardiac fibrosis fibroblast growth factor 21 Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/331b695e890d4d3e80f1343005995ade
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spelling	oai:doaj.org-article:331b695e890d4d3e80f1343005995ade2021-11-25T17:55:33ZExercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction10.3390/ijms2222123411422-00671661-6596https://doaj.org/article/331b695e890d4d3e80f1343005995ade2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12341https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-β1 (TGF-β1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and <i>Fgf21</i> knockout (<i>Fgf21</i> KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-β1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of <i>Fgf21</i> weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H<sub>2</sub>O<sub>2</sub> (100 μM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H<sub>2</sub>O<sub>2</sub>-induced activation of the TGF-β1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-β1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.Yixuan MaYixin KuangWenyan BoQiaoqin LiangWenfei ZhuMengxin CaiZhenjun TianMDPI AGarticleexercise trainingmyocardial infarctioncardiac fibrosisfibroblast growth factor 21Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12341, p 12341 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	exercise training myocardial infarction cardiac fibrosis fibroblast growth factor 21 Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	exercise training myocardial infarction cardiac fibrosis fibroblast growth factor 21 Biology (General) QH301-705.5 Chemistry QD1-999 Yixuan Ma Yixin Kuang Wenyan Bo Qiaoqin Liang Wenfei Zhu Mengxin Cai Zhenjun Tian Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction
description	Exercise training has been reported to alleviate cardiac fibrosis and ameliorate heart dysfunction after myocardial infarction (MI), but the molecular mechanism is still not fully clarified. Fibroblast growth factor 21 (FGF21) exerts a protective effect on the infarcted heart. This study investigates whether exercise training could increase FGF21 protein expression and regulate the transforming growth factor-β1 (TGF-β1)-Smad2/3-MMP2/9 signaling pathway to alleviate cardiac fibrosis following MI. Male wild type (WT) C57BL/6J mice and <i>Fgf21</i> knockout (<i>Fgf21</i> KO) mice were used to establish the MI model and subjected to five weeks of different types of exercise training. Both aerobic exercise training (AET) and resistance exercise training (RET) significantly alleviated cardiac dysfunction and fibrosis, up-regulated FGF21 protein expression, inhibited the activation of TGF-β1-Smad2/3-MMP2/9 signaling pathway and collagen production, and meanwhile, enhanced antioxidant capacity and reduced cell apoptosis in the infarcted heart. In contrast, knockout of <i>Fgf21</i> weakened the cardioprotective effects of AET after MI. In vitro, cardiac fibroblasts (CFs) were isolated from neonatal mice hearts and treated with H<sub>2</sub>O<sub>2</sub> (100 μM, 6 h). Recombinant human FGF21 (rhFGF21, 100 ng/mL, 15 h) and/or 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM, 15 h) inhibited H<sub>2</sub>O<sub>2</sub>-induced activation of the TGF-β1-Smad2/3-MMP2/9 signaling pathway, promoted CFs apoptosis and reduced collagen production. In conclusion, exercise training increases FGF21 protein expression, inactivates the TGF-β1-Smad2/3-MMP2/9 signaling pathway, alleviates cardiac fibrosis, oxidative stress, and cell apoptosis, and finally improves cardiac function in mice with MI. FGF21 plays an important role in the anti-fibrosis effect of exercise training.
format	article
author	Yixuan Ma Yixin Kuang Wenyan Bo Qiaoqin Liang Wenfei Zhu Mengxin Cai Zhenjun Tian
author_facet	Yixuan Ma Yixin Kuang Wenyan Bo Qiaoqin Liang Wenfei Zhu Mengxin Cai Zhenjun Tian
author_sort	Yixuan Ma
title	Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction
title_short	Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction
title_full	Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction
title_fullStr	Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction
title_full_unstemmed	Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction
title_sort	exercise training alleviates cardiac fibrosis through increasing fibroblast growth factor 21 and regulating tgf-β1-smad2/3-mmp2/9 signaling in mice with myocardial infarction
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/331b695e890d4d3e80f1343005995ade
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Exercise Training Alleviates Cardiac Fibrosis through Increasing Fibroblast Growth Factor 21 and Regulating TGF-β1-Smad2/3-MMP2/9 Signaling in Mice with Myocardial Infarction

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