Metabolic regulation of exercise-induced adaptation in striated muscle

摘要 有氧运动促进心脏有益的适应。先前的研究表明， 磷酸果糖激酶水平上心脏葡萄糖分解代谢的减少对于运动诱导的 心脏生长尽管这一发现将新陈代谢的变化与生长的启动联系起来，但 运动中葡萄糖代谢的变化以及代谢如何协调心脏生长仍然存在 不清楚代谢变化可以通过两种方式促进运动诱导的肌肉生长。第一， 运动期间糖酵解中间产物的水平可以调节构件生物合成的碳可用性， 其构成心肌细胞肥大的物质原因。第二，发生在 运动可以调节运动基因程序，这在运动性组织重塑中起重要作用。 然而，很难区分这两个原因对所带来的适应性的贡献。 以锻炼为主。解决这些问题需要了解代谢如何变化， 运动后，然后确定调节心肌细胞生长的代谢成分。在这 项目，我将测试的一般假设，高水平的竞争底物，如乳酸和脂肪酸 促进心脏中的辅助生物合成途径活性并驱动心脏生长的基因程序。到 了解葡萄糖代谢如何响应运动或在竞争的存在下发生变化 底物，我已经标准化了深度网络追踪方法，以测量体内葡萄糖衍生的碳命运 使用含13 C6-葡萄糖饮食的饮食递送。具体而言，目的是（1）定义心脏的变化， 葡萄糖代谢对运动训练的反应和（2）确定循环底物如何影响 心脏肥大信号和基因程序。这项研究计划将提供培训的关键领域，我 作为一名科学家的成长，并为我在运动科学领域的职业生涯做好准备。该项目将提供新鲜的 关于代谢如何调节心肌生长的观点，并可以确定创新的代谢 控制组织重塑或优化运动对心血管益处的方法。重要的是这些 研究将整合我们目前对横纹肌catalysts的理解与新的知识， 在肌肉组织内调节肌肉张力。

Abstract Aerobic exercise promotes beneficial adaptations in the heart. Previous studies demonstrate that transient reductions in cardiac glucose catabolism at the level of phosphofructokinase are important for exercise-induced cardiac growth. Although this finding links changes in metabolism with initiation of growth, the mechanisms by which glucose metabolism changes during exercise and how metabolism coordinates cardiac growth remain unclear. Metabolic changes could promote exercise-induced muscle growth in two ways. First, changes in the levels of glycolytic intermediates during exercise could regulate carbon availability for building block biosynthesis, which constitutes a material cause for cardiomyocyte hypertrophy. Second, metabolic changes that occur during exercise could regulate the exercise gene program, which is important for exercise-induced tissue remodeling. Nevertheless, it has been difficult to disentangle the contribution of these two causes to the adaptations brought forth by exercise. Addressing these problems requires understanding how metabolism changes both during and after exercise, and then identifying the metabolic components that modulate cardiomyocyte growth. In this project, I will test the general hypothesis that high levels of competing substrates such as lactate and fatty acids prompt ancillary biosynthetic pathway activity in the heart and drive gene programs for cardiac growth. To understand how glucose metabolism changes in response to exercise or in the presence of competing substrates, I have standardized deep network tracing methods to measure glucose-derived carbon fate in vivo using dietary delivery of a 13C6-glucose-containing diet. Specifically, the aims are (1) to define changes in cardiac glucose metabolism in response to exercise training and (2) to determine how circulating substrates influence cardiac hypertrophic signaling and gene programs. This research plan will provide training in areas critical to my growth as a scientist and prepare me for a career in the exercise sciences. The project will provide fresh perspectives about how metabolism regulates cardiac muscle growth and could identify innovative metabolic approaches to control tissue remodeling or optimize the cardiovascular benefits of exercise. Importantly, these studies will integrate our current understanding of striated muscle catabolism with new knowledge of how anabolism is regulated within muscle tissue.