Myocardial Biology Unit, Boston University School of Medicine, Boston, MA, United States.
Myocardial Biology Unit, Boston University School of Medicine, Boston, MA, United States; Heart Failure Unit, School of Medicine and Public Health, University of Newcastle, NSW 2300, Australia.
J Mol Cell Cardiol. 2018 Mar;116:106-114. doi: 10.1016/j.yjmcc.2018.01.017. Epub 2018 Feb 1.
Metabolic syndrome is a cluster of obesity-related metabolic abnormalities that lead to metabolic heart disease (MHD) with left ventricular pump dysfunction. Although MHD is thought to be associated with myocardial energetic deficiency, two key questions have not been answered. First, it is not known whether there is a sufficient energy deficit to contribute to pump dysfunction. Second, the basis for the energy deficit is not clear. To address these questions, mice were fed a high fat, high sucrose (HFHS) 'Western' diet to recapitulate the MHD phenotype. In isolated beating hearts, we used P NMR spectroscopy with magnetization transfer to determine a) the concentrations of high energy phosphates ([ATP], [ADP], [PCr]), b) the free energy of ATP hydrolysis (∆G), c) the rate of ATP production and d) flux through the creatine kinase (CK) reaction. At the lowest workload, the diastolic pressure-volume relationship was shifted upward in HFHS hearts, indicative of diastolic dysfunction, whereas systolic function was preserved. At this workload, the rate of ATP synthesis was decreased in HFHS hearts, and was associated with decreases in both [PCr] and ∆G. Higher work demands unmasked the inability of HFHS hearts to increase systolic function and led to a further decrease in ∆G to a level that is not sufficient to maintain normal function of sarcoplasmic Ca-ATPase (SERCA). While [ATP] was preserved at all work demands in HFHS hearts, the progressive increase in [ADP] led to a decrease in ∆G with increased work demands. Surprisingly, CK flux, CK activity and total creatine were normal in HFHS hearts. These findings differ from dilated cardiomyopathy, in which the energetic deficiency is associated with decreases in CK flux, CK activity and total creatine. Thus, in HFHS-fed mice with MHD there is a distinct metabolic phenotype of the heart characterized by a decrease in ATP production that leads to a functionally-important energetic deficiency and an elevation of [ADP], with preservation of CK flux.
代谢综合征是一组与肥胖相关的代谢异常，可导致左心室泵功能障碍的代谢性心脏病（MHD）。尽管认为 MHD 与心肌能量不足有关，但有两个关键问题尚未得到解答。首先，尚不清楚是否存在足够的能量不足来导致泵功能障碍。其次，能量不足的基础尚不清楚。为了解决这些问题，我们用高脂肪、高蔗糖（HFHS）“西式”饮食喂养小鼠来重现 MHD 表型。在分离的搏动心脏中，我们使用 P NMR 光谱和磁化转移来确定 a）高能磷酸化合物（[ATP]、[ADP]、[PCr]）的浓度，b）ATP 水解的自由能（∆G），c）ATP 生成率，d）通过肌酸激酶（CK）反应的通量。在最低工作负荷下，HFHS 心脏的舒张压力-容积关系向上移位，表明舒张功能障碍，而收缩功能正常。在这个工作负荷下，HFHS 心脏的 ATP 合成率降低，并且与 [PCr]和 ∆G 的降低有关。更高的工作需求揭示了 HFHS 心脏无法增加收缩功能的能力，并导致 ∆G 进一步降低到不足以维持肌浆网 Ca-ATP 酶（SERCA）正常功能的水平。虽然在 HFHS 心脏的所有工作需求中都保留了 [ATP]，但随着工作需求的增加，[ADP]的逐渐增加导致 ∆G 降低。令人惊讶的是，HFHS 心脏中的 CK 通量、CK 活性和总肌酸正常。这些发现与扩张型心肌病不同，在扩张型心肌病中，能量不足与 CK 通量、CK 活性和总肌酸的降低有关。因此，在患有 MHD 的 HFHS 喂养小鼠中，心脏存在明显的代谢表型，其特征是 ATP 生成减少导致功能重要的能量不足和 [ADP]升高，同时 CK 通量保持不变。
