Metabolic regulation of exercise-induced adaptation in striated muscle

横纹肌运动诱导适应的代谢调节

基本信息

批准号：
10473603
负责人：
Kyle Fulghum
金额：
$ 1.32万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473603
关键词：
Address Adipose tissue Aerobic Exercise Affect Anabolism Area Blood capillaries Carbohydrates Carbon Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Catabolism Data Diet Enzyme Activation Enzymes Exercise FRAP1 gene Fatty Acids Genes Genetic Glucose Glucosephosphate Dehydrogenase Glucosephosphate Isomerase Glycolysis Growth Heart Hypertrophy In Vitro Insulin-Like Growth Factor I Ketones Knowledge Link Liquid substance Mass Spectrum Analysis Measures Metabolic Metabolic Pathway Metabolism Methods Molecular Mus Muscle Myocardial Myocardium Nucleotides Pathway interactions Pharmacology Phospholipids Phosphotransferases Production Regulation Research Role Science Scientist Signal Pathway Signal Transduction Standardization Stimulus Striated Muscles Study Subject Testing Tissues Training aminoacid biosynthesis carbohydrate metabolism career density dietary effective intervention energy balance exercise training glucose metabolism heart function in vivo innovation interest macromolecule novel prevent programs pyruvate dehydrogenase respiratory response

项目摘要

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.

抽象的有氧运动促进心脏中的有益适应。先前的研究表明了瞬态在磷酸果果酶水平上的心脏葡萄糖分解代谢的降低对于运动诱导很重要心脏增长。尽管这一发现将新陈代谢的变化与增长的启动联系起来，但该机制通过运动过程中哪些葡萄糖代谢发生变化，以及代谢如何坐在心脏增长保持不清楚。代谢变化可以通过两种方式促进运动引起的肌肉生长。首先，变化运动过程中的糖酵解中间体水平可以调节碳的可利用性，以使构建块生物合成，这构成了心肌细胞肥大的物质原因。其次，在运动可以调节运动基因程序，这对于运动引起的组织重塑很重要。然而，很难解除这两个原因对所带来的改编的贡献通过锻炼。解决这些问题需要了解新陈代谢在和运动后，然后确定调节心肌细胞生长的代谢成分。在这个项目，我将测试一个普遍的假设，即乳酸和脂肪酸等高水平的竞争底物促使心脏中辅助生物合成途径活性，并驱动基因程序以进行心脏生长。到了解葡萄糖代谢如何在运动中或在竞争的情况下发生变化底物，我已经标准化了深网追踪方法，以测量体内葡萄糖衍生的碳命运使用含有13C6-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响应运动训练和（2）确定循环底物如何影响心脏肥厚的信号传导和基因程序。该研究计划将在对我的重要领域提供培训作为科学家成长，为我从事运动科学的职业做好准备。该项目将提供新鲜关于新陈代谢如何调节心脏肌肉生长的观点并可以识别创新的代谢控制组织重塑或优化运动的心血管益处的方法。重要的是，这些研究将使我们当前对横纹肌肉分解代谢的理解与有关如何的新知识代谢在肌肉组织中受到调节。