Liu Yanna, Wang Li, Jiao Sirui, Yang Xiaohan, Liu Gang, Fan Kai, Zhao Henan, Ma Jianmei
Department of Anatomy, Dalian Medical University, Dalian, People's Republic of China.
Department of Pathophysiology, Dalian Medical University, Dalian, People's Republic of China.
J Appl Physiol (1985). 2025 Mar 1;138(3):746-760. doi: 10.1152/japplphysiol.00275.2024. Epub 2025 Jan 28.
Exercise in heart failure with preserved ejection fraction (HFpEF) remains a hot topic, although current treatment strategies have not been shown to improve the long-term prognosis of HFpEF. Previous studies have mostly focused on the roles of endurance training; the mechanisms underlying long-term voluntary exercise have not been elucidated. The purpose of the present analysis was to evaluate alterations in cardiac function in HFpEF mice (HFpEF-Sed) after 6 wk of voluntary running (HFpEF-Ex), investigate mechanisms, and compare the effects with fluoxetine (HFpEF-FLX). We found that voluntary exercise, instead of fluoxetine intervention, significantly improved left ventricular end-diastolic internal diameter (LVIDd) and the rate of change in anterior wall thickness (AWT) in HFpEF mice. The exercise capacity of HFpEF-Sed mice was significantly reduced, but prolonged voluntary running significantly reversed the expression of myocardial brain natriuretic peptide (BNP), TNF-α, and IL-6, α-myosin heavy chain (α-MHC), and β-MHC in HFpEF-Sed mice, along with myocardial fiber disorders accompanied by massive inflammatory cell infiltrates. Importantly, myocardial complex III and complex V, Mfn2, Drp1, p62, and LC3 II/I expression in HFpEF-Sed mice were all significantly different from those of normal mice, whereas voluntary exercise significantly reversed these expressions. These findings strongly suggest that long-term voluntary exercise is effective in avoiding acute and chronic energy stress in HFpEF-Sed mice, which is consistent with the mechanism of current first-line treatment for HFpEF. This notion was further supported by electron microscopy results, which showed no pathological features in cardiomyocyte mitochondrial morphology after prolonged voluntary exercise. In addition, fluoxetine was found to inhibit depressive-like behavior in HFpEF mice. As a self-initiating, self-sustaining, and low-cost treatment for patients with heart failure, how voluntary exercise plays its roles in interfering with the pathophysiologic pathways associated with HFpEF is still largely unknown. The results of this study indicate that long-term voluntary exercise can effectively antagonize acute and chronic dual-energy stress and avoid diastolic function limitation caused by pathological ventricular remodeling.
射血分数保留的心力衰竭（HFpEF）中的运动仍然是一个热门话题，尽管目前的治疗策略尚未显示能改善HFpEF的长期预后。先前的研究大多集中在耐力训练的作用上；长期自主运动的潜在机制尚未阐明。本分析的目的是评估HFpEF小鼠（HFpEF-Sed）在6周自主跑步（HFpEF-Ex）后心脏功能的变化，研究其机制，并与氟西汀（HFpEF-FLX）的效果进行比较。我们发现，与氟西汀干预相比，自主运动显著改善了HFpEF小鼠的左心室舒张末期内径（LVIDd）和前壁厚度变化率（AWT）。HFpEF-Sed小鼠的运动能力显著降低，但长期自主跑步显著逆转了HFpEF-Sed小鼠中心肌脑钠肽（BNP）、TNF-α、IL-6、α-肌球蛋白重链（α-MHC）和β-MHC的表达，以及伴有大量炎性细胞浸润的心肌纤维紊乱。重要的是，HFpEF-Sed小鼠中的心肌复合体III和复合体V、Mfn2、Drp1、p62和LC3 II/I表达均与正常小鼠有显著差异，而自主运动显著逆转了这些表达。这些发现强烈表明，长期自主运动能有效避免HFpEF-Sed小鼠的急性和慢性能量应激，这与目前HFpEF一线治疗的机制一致。电子显微镜结果进一步支持了这一观点，该结果显示长期自主运动后心肌细胞线粒体形态无病理特征。此外，还发现氟西汀可抑制HFpEF小鼠的抑郁样行为。作为一种对心力衰竭患者自发、自我维持且低成本的治疗方法，自主运动如何在干扰与HFpEF相关的病理生理途径中发挥作用仍 largely unknown。本研究结果表明，长期自主运动可有效对抗急性和慢性双能量应激，并避免病理性心室重塑导致的舒张功能受限。
