Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom; Centre for Health and Life Sciences, Coventry University, Coventry, United Kingdom.
Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom.
Atherosclerosis. 2024 Dec;399:118599. doi: 10.1016/j.atherosclerosis.2024.118599. Epub 2024 Sep 17.
Peroxisome proliferator-activated receptor α (PPARα) is crucial for regulating cardiac β-oxidation in the heart, liver, and kidney. Ageing can induce cardiac metabolic alterations, but the role of PPARα has not been extensively characterised. The aim of this research was to investigate the role of PPARα in the aged heart.
Hyperpolarized [1-C]pyruvate was used to evaluate in vivo cardiac carbohydrate metabolism in fed and fasted young (3 months) and old (20-22 months) PPARα knockout (KO) mice versus controls. Cine MRI assessed cardiac structural and functional changes. Cardiac tissue analysis included qRT-PCR and Western blotting for Pparα, medium chain acyl-CoA dehydrenase (MCAD), uncoupling protein (UCP) 3, glucose transporter (GLUT) 4 and PDH kinase (PDK) 1,2, and 4 expression.
PPARα-KO hearts from both young and old mice showed significantly reduced Pparα mRNA and a 58-59 % decrease in MCAD protein levels compared to controls. Cardiac PDH flux was similar in young control and PPARα-KO mice but 96 % higher in old PPARα-KO mice. Differences between genotypes were consistent in fed and fasted states, with reduced PDH flux when fasted. Increased PDH flux was accompanied by a 179 % rise in myocardial GLUT4 protein. No differences in PDK 1, 2, or 4 protein levels were observed between fed groups, indicating the increased PDH flux in aged PPARα-KO mice was not due to changes in PDH phosphorylation.
Aged PPARα-KO mice demonstrated higher cardiac PDH flux compared to controls, facilitated by increased myocardial GLUT4 protein levels, leading to enhanced glucose uptake and glycolysis.
过氧化物酶体增殖物激活受体α（PPARα）对于心脏、肝脏和肾脏中的β-氧化至关重要。衰老会导致心脏代谢改变，但 PPARα 的作用尚未得到广泛研究。本研究旨在探究 PPARα 在衰老心脏中的作用。
在喂食和禁食的年轻（3 个月）和年老（20-22 个月）PPARα 敲除（KO）小鼠与对照相比，使用 1-C 标记的丙酮酸评估体内心脏碳水化合物代谢。电影 MRI 评估心脏结构和功能变化。心脏组织分析包括 qRT-PCR 和 Western blot 检测 Pparα、中链酰基辅酶 A 脱氢酶（MCAD）、解偶联蛋白（UCP）3、葡萄糖转运蛋白（GLUT）4 和 PDH 激酶（PDK）1、2、4 的表达。
年轻和年老的 PPARα-KO 小鼠心脏的 Pparα mRNA 明显降低，MCAD 蛋白水平降低 58-59%。年轻对照和 PPARα-KO 小鼠的心脏 PDH 通量相似，但年老 PPARα-KO 小鼠的 PDH 通量高 96%。在喂食和禁食状态下，基因型之间的差异一致，禁食时 PDH 通量降低。PDH 通量增加伴随着心肌 GLUT4 蛋白增加 179%。喂食组 PDK 1、2 或 4 蛋白水平无差异，表明年老 PPARα-KO 小鼠 PDH 通量增加不是由于 PDH 磷酸化的变化。
与对照相比，年老的 PPARα-KO 小鼠表现出更高的心脏 PDH 通量，这是由心肌 GLUT4 蛋白水平增加介导的，导致葡萄糖摄取和糖酵解增强。
