Gibb Andrew A, Epstein Paul N, Uchida Shizuka, Zheng Yuting, McNally Lindsey A, Obal Detlef, Katragadda Kartik, Trainor Patrick, Conklin Daniel J, Brittian Kenneth R, Tseng Michael T, Wang Jianxun, Jones Steven P, Bhatnagar Aruni, Hill Bradford G
Institute of Molecular Cardiology (A.A.G., Y.Z., L.A.M., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).
Diabetes and Obesity Center (A.A.G., Y.Z., L.A.M., D.O., K.K., P.T., D.J.C., K.R.B., S.P.J., A.B., B.G.H.).
Circulation. 2017 Nov 28;136(22):2144-2157. doi: 10.1161/CIRCULATIONAHA.117.028274. Epub 2017 Aug 31.
Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth.
We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart.
Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (Glyco mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of Glyco mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (Glyco mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling.
Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.
运动可促进心脏的代谢重塑，这与生理性心脏生长相关；然而，尚不清楚体力活动引起的心脏代谢变化是否以及如何导致心肌重塑。在本研究中，我们测试了运动介导的心肌细胞葡萄糖代谢变化对生理性心脏生长是否重要。
我们使用放射性、免疫、代谢组学和生化分析方法来测量急性和慢性跑步机运动小鼠心肌葡萄糖代谢的变化。为了评估糖酵解活性变化的相关性，我们确定了6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶突变形式的心脏特异性表达如何影响心脏结构、功能、代谢以及与心脏重塑相关的基因程序。代谢组学和转录组学筛选用于鉴定心脏中受糖酵解活性调节的代谢途径和基因集。
运动通过调节循环底物和降低磷酸果糖激酶活性急性降低了通过糖酵解的葡萄糖利用；然而，在运动适应后的恢复状态下，心肌磷酸果糖激酶活性和糖酵解增加。在小鼠中，激酶缺陷型6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶转基因（Glyco小鼠）的心脏特异性表达降低了糖酵解速率并调节了已知促进心脏生长的基因的表达。Glyco小鼠的心脏有更大的心肌细胞、增强的心脏功能和更高的毛细血管与心肌细胞比率。心脏中磷酸酶缺陷型6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（Glyco小鼠）的表达增加了葡萄糖利用并促进了一种更具病理性的肥大形式，而没有生理性心脏生长程序的转录激活。磷酸果糖激酶活性的调节足以调节心脏中的葡萄糖-脂肪酸循环；然而，由始终低或高的磷酸果糖激酶活性引起的代谢不灵活性导致适度的线粒体损伤。转录组学分析表明，糖酵解调节参与心脏代谢和重塑的关键基因的表达。
运动诱导的糖酵解活性降低刺激生理性心脏重塑，并且代谢灵活性对于维持心脏中的线粒体健康很重要。
