Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Basic Res Cardiol. 2020 Mar 31;115(3):28. doi: 10.1007/s00395-020-0787-1.
This study aims to determine the effect of exercise on the cardiac function, metabolic profiles and related molecular mechanisms in mice with ischemic-induced heart failure (HF). HF was induced by myocardial infarction (MI) in C57BL6/N mice. Cardiac function and physical endurance were improved in HF mice after exercise. Micro-PET/CT scanning revealed enhanced myocardial glucose uptake in vivo in HF mice after exercise. Exercise reduced mitochondrial structural damage in HF mice. Cardiomyocytes isolated from HF + exercise mice showed increased glycolysis capacity, respiratory function and ATP production. Both mRNA and protein expression of glucose transporter 1 (GLUT1) were upregulated after exercise. Results of ChIP-PCR revealed a novel interaction between transcription factor myocyte enhancer factor 2a (MEF2a) and GLUT1 in hearts of HF + exercise mice. Exercise also activated myocardial AMP-activated protein kinase (AMPK), which in turn phosphorylated histone deacetylase 4 (HDAC4), and thereby modulated the GLUT1 expression through reducing its inhibition on MEF2a in HF mice. Inhibition of HDAC4 also improved cardiac function in HF mice. Moreover, knockdown of GLUT1 impaired the systolic and diastolic function of isolated cardiomyocytes. In conclusion, exercise improves cardiac function and glucose metabolism in HF mice through inhibiting HDAC4 and upregulating GLUT1 expression.
本研究旨在探讨运动对缺血性心力衰竭（HF）诱导的小鼠心脏功能、代谢特征及相关分子机制的影响。通过心肌梗死（MI）诱导 C57BL6/N 小鼠发生 HF。运动可改善 HF 小鼠的心脏功能和体力耐力。微 PET/CT 扫描显示，运动后 HF 小鼠的心肌葡萄糖摄取能力增强。运动减轻了 HF 小鼠的线粒体结构损伤。与 HF 小鼠相比，HF+运动组的心肌细胞的糖酵解能力、呼吸功能和 ATP 生成增加。运动后葡萄糖转运蛋白 1（GLUT1）的 mRNA 和蛋白表达均上调。ChIP-PCR 结果显示，运动后 HF+运动组小鼠心脏中存在转录因子肌细胞增强因子 2a（MEF2a）与 GLUT1 的新的相互作用。运动还激活了心肌 AMP 激活的蛋白激酶（AMPK），从而磷酸化组蛋白去乙酰化酶 4（HDAC4），减少其对 HF 小鼠 MEF2a 的抑制，从而调节 GLUT1 的表达。抑制 HDAC4 也可改善 HF 小鼠的心脏功能。此外，敲低 GLUT1 会损害分离的心肌细胞的收缩和舒张功能。总之，运动通过抑制 HDAC4 和上调 GLUT1 表达来改善 HF 小鼠的心脏功能和葡萄糖代谢。
