Date on Master's Thesis/Doctoral Dissertation
Physiology and Biophysics
Physiology and Biophysics, PhD
Committee Co-Chair (if applicable)
exercise; glycolysis; hypertrophy/remodeling; metabolomics; mitochondria; stable isotope
While the benefits of exercise affect several organs, a significant adaptive response occurs within the heart. Exercise promotes cardiac growth, increases angiogenesis, and enhances cardiac function and these adaptations are associated with a cardioprotective phenotype. Additionally, extensive evidence shows that exercise dynamically regulates myocardial metabolism. This can be attributed to both changes in hormonal stimulation, increases in bioenergetic demand, and the bioavailability of circulating substrates. However, it is unclear whether these changes in metabolism contribute to physiologic cardiac growth. We reason that exercise-induced changes in metabolism are required to balance the catabolic and anabolic reactions needed for growth. Specifically, we hypothesize that exercise-induced changes in myocardial glycolytic activity are essential for activation of the physiological growth program and the synthesis of metabolites required for growth. Prior to investigating the effects of exercise on cardiac metabolism, we established a model of cardiac adaptation to exercise training in mice (Chapter II). Once established, as discussed in Chapter III, we found that the exercise-adapted heart demonstrates enhanced glycolytic activity; however, during exercise glycolytic rate in the heart is diminished. To determine whether high or low glycolytic rates may be a stimulus for cardiac growth, we assessed the effect of cardiac-specific overexpression of phosphofructokinase isoforms that decrease or increase myocardial glycolytic rate. We found that constitutive reduction in glycolytic rate was sufficient to structurally and functionally phenocopy the exercise-adapted heart, replete with activation of the physiologic growth program; however, metabolic inflexibility invoked by constitutive changes in glycolysis results in mild mitochondrial dysfunction. To assess how glycolytic activity affects anabolic metabolism, we utilized stable isotope labeling in an in vitro model to interrogate flux of carbon into collateral biosynthetic pathways of glucose metabolism. Results from these studies, discussed in Chapter IV, show that PFK1 and glycolytic activity coordinate the allocation of glucose into pathways that would be important for cardiac growth. Collectively, our results indicate that physiological growth of the heart is intricately regulated by exercise-induced changes in intermediary metabolism, and that preservation of metabolic flexibility is essential for mitochondrial health. Importantly, these findings suggest a causal role of metabolism in myocardial responses to stress.
Gibb, Andrew Alan, "Metabolic regulation of myocardial adaptation to exercise." (2017). Electronic Theses and Dissertations. Paper 2878.
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