Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Yliopistonranta 1 C, Kuopio, Finland.
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neulaniementie 2, Kuopio, Finland.
Cardiovasc Res. 2019 Jan 1;115(1):107-118. doi: 10.1093/cvr/cvy155.
Heart failure (HF) is associated with drastic changes in metabolism leading to a cardiac energy deficiency well as maladaptive changes in multiple other tissues. It is still unclear which of these changes originates from cardiomyocyte metabolic remodelling or whether they are induced secondarily by systemic factors. Our aim here was to induce cardiac restricted metabolic changes mimicking those seen in HF and to characterize the associated metabolite changes in the heart, circulation, and peripheral tissues.
We generated a cardiac specific PGC-1α knockout mice (KO) to specifically induce metabolic dysregulation typically accompanied by HF and performed a non-targeted LC-MS metabolite profiling analysis of heart, plasma, liver, and skeletal muscle to identify metabolites associated with cardiac specific metabolic remodelling. The KO animals developed a progressive cardiomyopathy with cardiac dilatation leading to fatal HF. At 17 weeks of age, when significant remodelling had occurred but before the onset of HF, isolated PGC-1α deficient cardiomyocytes had suppressed glucose and fatty acid oxidation as well as blunted anaerobic metabolism. KO hearts displayed a distinctive metabolite profile with 92 significantly altered molecular features including metabolite changes in energy metabolism, phospholipid metabolism, amino acids, and oxidative stress signalling. Some of the metabolite changes correlated with the specific parameters of cardiac function. We did not observe any significant alterations in the metabolomes of the other measured tissues or in plasma.
Heart specific PGC-1α KO induces metabolic, functional, and structural abnormalities leading to dilating cardiomyopathy and HF. The metabolic changes were limited to the cardiac tissue indicating that cardiomyocyte metabolic remodelling is not sufficient to evoke the body wide metabolic alterations usually associated with HF.
心力衰竭（HF）与代谢的剧烈变化有关，导致心肌能量不足，以及其他多种组织的适应性变化。目前尚不清楚这些变化是源自心肌细胞代谢重塑，还是由全身因素继发引起的。我们的目的是诱导心脏特异性代谢变化，模拟 HF 中所见的变化，并在心脏、循环和外周组织中描述相关的代谢物变化。
我们生成了心脏特异性过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）敲除小鼠（KO），以专门诱导通常伴随 HF 发生的代谢失调，并对心脏、血浆、肝脏和骨骼肌进行非靶向 LC-MS 代谢物谱分析，以鉴定与心脏特异性代谢重塑相关的代谢物。KO 动物发生进行性扩张型心肌病，导致心脏扩张和致命性 HF。在 17 周龄时，当发生明显的重塑但尚未发生 HF 时，分离的 PGC-1α 缺陷型心肌细胞的葡萄糖和脂肪酸氧化受到抑制，无氧代谢减弱。KO 心脏表现出独特的代谢谱，有 92 个显著改变的分子特征，包括能量代谢、磷脂代谢、氨基酸和氧化应激信号的代谢物变化。一些代谢物变化与特定的心脏功能参数相关。我们在其他测量的组织或血浆中未观察到任何代谢物谱的显著变化。
心脏特异性 PGC-1α KO 诱导代谢、功能和结构异常，导致扩张型心肌病和 HF。代谢变化仅限于心脏组织，表明心肌细胞代谢重塑不足以引起通常与 HF 相关的全身性代谢改变。
