Metabolic regulation of exercise-induced adaptation in striated muscle

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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.