State Key Laboratory of Pharmaceutical Biotechnology (L.J., L.G., L.Y., L.S., R.Y., Y.L., Yao Wang, Y.C., X.J., Q.W., X.Y., B.L., C.W.H.W., Yu Wang, Z.X., Q.L., A.X.), University of Hong Kong, China.
Department of Medicine (L.J., L.G., L.S., R.Y., Y.L., Yao Wang, X.J., Q.W., X.Y., J.L., Z.X., Q.L., A.X.), University of Hong Kong, China.
Circulation. 2022 Nov 15;146(20):1537-1557. doi: 10.1161/CIRCULATIONAHA.122.059631. Epub 2022 Sep 22.
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.
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.
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.
The FGF21-SIRT3 axis mediates the protective effects of exercise against DCM by preserving mitochondrial integrity and represents a potential therapeutic target for DCM.
URL: https://www.
gov; Unique identifier: NCT03240978.
运动是一种有效的非药物策略，可以通过尚未明确的机制来缓解糖尿病心肌病（DCM）。成纤维细胞生长因子 21（FGF21）是一种具有心脏代谢稳态多效益处的肽激素，已被确定为运动反应因子。本研究旨在探讨 FGF21 信号是否介导运动对 DCM 的益处，如果是这样，阐明其潜在机制。
通过高脂肪饮食喂养和链脲佐菌素注射诱导 DCM，使全身性或肝细胞特异性 FGF21 敲除小鼠、心肌细胞特异性β-klotho（FGF21 的必需共受体）敲除小鼠及其野生型同窝仔鼠接受 6 周运动干预，并评估心脏功能。通过电子显微镜、酶测定以及脂肪酸氧化和 ATP 产生的测量来评估心脏线粒体结构和功能。用人诱导多能干细胞衍生的心肌细胞来研究受体和受体后信号通路，这些通路赋予 FGF21 对抗有毒脂质诱导的线粒体功能障碍的保护作用。
跑步机运动显著诱导β-klotho 在心脏中的表达，并显著减轻野生型小鼠中糖尿病引起的心脏功能障碍，同时减少心脏中线粒体损伤和增加线粒体酶活性。然而，在全身性或肝细胞特异性敲除 FGF21 或心肌细胞特异性敲除β-klotho 的小鼠中，运动的这种心脏保护益处则大大丧失。从机制上讲，运动增强了 FGF21 的心脏作用，通过 AMPK 诱导的 FOXO3 磷酸化来诱导线粒体去乙酰化酶 SIRT3 的表达，从而逆转糖尿病引起的一组线粒体酶的过度乙酰化和功能障碍。FGF21 通过诱导 AMPK/FOXO3/SIRT3 信号轴在人诱导多能干细胞衍生的心肌细胞中预防有毒脂质引起的线粒体功能障碍和氧化应激。腺相关病毒介导的心脏 SIRT3 表达的恢复足以恢复糖尿病 FGF21 敲除小鼠对运动的反应性，从而改善线粒体功能障碍和 DCM。
FGF21-SIRT3 轴通过维持线粒体完整性来介导运动对 DCM 的保护作用，代表了 DCM 的一个潜在治疗靶点。
网址：www.clinicaltrials.gov；独特标识符：NCT03240978。
