Date on Master's Thesis/Doctoral Dissertation

12-2022

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Hill, Bradford

Committee Co-Chair (if applicable)

Jones, Steven

Committee Member

Jones, Steven

Committee Member

LeBlanc, Amanda

Committee Member

Schuschke, Dale

Committee Member

Maldonado, Claudio

Author's Keywords

Exercise; metabolism; cardiac; hypertrophy; glucose

Abstract

Regular aerobic exercise promotes physiological cardiac growth, which is an adaptive response thought to enable the heart to meet higher physical demands. Cardiac growth involves coordination of catabolic and anabolic activities to support ATP generation, macromolecule biosynthesis, and myocyte hypertrophy. Although previous studies suggest that exercise-induced reductions in cardiac glycolysis are critical for physiological myocyte hypertrophy, it remains unclear how exercise influences the many interlinked pathways of metabolism that support adaptive remodeling of the heart. In this thesis project, we tested the general hypothesis that aerobic exercise promotes physiological cardiac growth by coordinating myocardial metabolism to promote glucose-supported anabolic pathway activity. Because little is known about how cardiac mitochondria adapt to exercise, we first characterized exercise-induced changes in murine cardiac mitochondrial metabolism and found that treadmill exercise has minimal effects on respiration and does not influence ADP sensitivity in the isolated organelle (Chapter II). These findings indicate that increases in cardiac mitochondrial respiration during exercise likely occur via changes in mitochondrial substrate abundance or via allosteric regulation of metabolic enzymes. To better describe how exercise influences cardiac metabolism in vivo, we examined changes in cardiac metabolite abundance via untargeted metabolomics. Although exercise altered metabolite abundances in female hearts more than male hearts, physiological cardiac growth was evident only in male hearts. Nevertheless, in both male and female hearts, exercise increased circulating and intracardiac ketone bodies and branched-chain amino acids (BCAAs). The idea that exercise-induced elevations in BCAAs are critical for exercise-induced cardiac growth is suggested by data showing that a diet deficient in BCAAs prevents cardiac growth following a treadmill exercise training program (Chapter III). We next standardized a noninvasive method for delivering 13C6-labeled glucose to mice via liquid diet. Paired with resolution mass spectrometry, this method enables insight into relationships between anabolic and catabolic pathways in the heart. We found that low cardiac phosphofructokinase (PFK) activity, which occurs transiently during a bout of intense treadmill exercise, increases glycogen storage and promotes biosynthesis of 5-aminoimidazole-4-carboxyamide ribonucleotide (AICAR). In vivo stable isotope tracing paired with native protein complex separation suggest that elevated levels of AICAR that occur with low PFK activity occur via formation of a multimeric complex containing several metabolic enzymes that appear to promote metabolic channeling (Chapter IV). We then performed deep network tracing following various durations of exercise training and found that cardiac glucose oxidation, amino acid synthesis, Krebs cycle activity, and glycogen synthesis increase in the early phases of an exercise training program, but progressively return to levels observed in non-exercised hearts following 4 weeks of training (Chapter V). Collectively, the findings of this thesis project provide a new working model of exercise-induced cardiac growth. Our data suggest that glucose-derived carbon is a major source of both energy and building material for the remodeling heart that integrates with BCAA metabolism to promote physiological cardiac growth.

Download

Share

COinS