Cardiomyocyte-Specific Deficiency of Ketone Body Metabolism Promotes Accelerated Pathological Remodeling
Biology and Biomedical Sciences: Molecular Cell Biology
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Peter A Crawford
During evolution of adverse ventricular remodeling that culminates in cardiomyopathy and congestive heart failure, myocardial fuel utilization becomes inefficient and inflexible, and mechanistic studies in pre-clinical models indicate that altered substrate and energy metabolism can cause cardiomyopathy. Therefore, deeper understanding and, ultimately, judicious nutritional and pharmacological manipulation of myocardial metabolism are expected to improve morbidity and mortality attributable to heart failure. While the roles of the primary myocardial fuels, fatty acids and glucose, in myocardial homeostasis and disease have been explored extensively, the influence of ketone bodies, which are highly competitive substrates for myocardial oxidative metabolism, remains ill-defined, in part due to their low circulating concentrations in fed states. Here I illuminate the roles of myocardial ketone body metabolism during states of both physiological and pathological clinical significance using customized ketogenic diets, measurements of systems physiology, evaluation of substrate utilization using 13C-edited proton nuclear magnetic resonance, measurements of mitochondrial bioenergetics, and in vivo high-resolution echocardiographic quantification of hemodynamics. Because the liver is the source of circulating ketone bodies, studies examining myocardial ketone body metabolism are dependent on hepatic physiology during periods of increased ketone body catabolism, including adherence to ketogenic diets. Therefore, my earliest studies examining a commonly used rodent ketogenic diet that is very high in fat, very low in carbohydrate, and choline restricted demonstrated that while the diet does provoke robust ketosis, it also causes significant hepatic steatosis, inflammation, and cellular injury. These preliminary studies thus necessitated the development of improved ketogenic diets that promote increased ketone body circulation in the absence of extraneous pathologies, which I found to be possible through the repletion of dietary choline. Nonetheless, the effect of ketogenic diets on cardiac function and myocardial bioenergetics remained to be elucidated. Having found that the adherence of wild type mice to ketogenic diet is well-tolerated and causes only subtle hemodynamic effects, I focused my studies on mice that exhibit loss of succinyl-CoA:3-oxoacid-CoA transferase (SCOT), which is required for terminal oxidation of ketone bodies, specifically in cardiac myocytes. While germline SCOT-knockout (KO) mice die in the early postnatal period, mice with cardiomyocyte-specific loss of SCOT (SCOT-Heart-KO) exhibit no overt metabolic abnormalities, and no differences in left ventricular mass or impairments of systolic function during periods of ketosis, including fasting and adherence to ketogenic diet. To determine the role of ketone body oxidation in the remodeling ventricle under pathological conditions, which are often associated with alterations in myocardial fuel utilization, I induced pressure overload injury through transverse aortic constriction (TAC) on SCOT-Heart-KO mice and observed adverse ventricular remodeling, including markedly increased left ventricular volume and diminished ejection fraction relative to control mice. Finally, I demonstrated that increased signatures of reactive oxygen species in SCOT-Heart-KO likely preceded adverse remodeling post-TAC, and that the signs of cardiomyopathy in SCOT-Heart-KO mice were attenuated when antioxidants are supplied to the mice post-TAC. These studies demonstrate the ability of myocardial ketone metabolism to coordinate the myocardial response to pressure overload, and support the theory that the oxidation of ketone bodies may be an important contributor to free radical homeostasis and hemodynamic preservation in the injured heart.
Schugar, Rebecca, "Cardiomyocyte-Specific Deficiency of Ketone Body Metabolism Promotes Accelerated Pathological Remodeling" (2014). All Theses and Dissertations (ETDs). 1386.