Despite major treatment advances over the last decades, mortality after the onset of heart failure (HF) symptoms remains extremely high. Changes in cardiac metabolic pathways, a process termed metabolic remodeling, precedes the structural remodeling that occurs with HF progression. During HF, branched-chain amino acids (BCAA) and branched-chain ketoacids (BCKA) increase in circulation. Moreover, the cardiac BCAA metabolic pathway becomes impaired, leading to increased cardiac BCAA and BCKA. The impact of systemic and cardiac-specific BCAA dysregulation on HF pathogenesis is still largely unknown. Using animal models of HF, we have found that HF per se impairs hepatic BCAA metabolism, which may explain the increase in circulating BCAA and BCKA. Additionally, we have found that, in contrast to previous reports, there is negligible entry of cardiac BCAA into the TCA cycle (i.e. anaplerosis). Rather, the heart tends to salvage the BCAA pool through conversion of BCKA into BCAA. Taken together, these findings suggest an unappreciated metabolic interplay between the heart and liver that increases delivery of BCAA and BCKA to the failing heart. Moreover, cardiac BCAA metabolism appears to affect the metabolism of other substrates such as glucose and fatty acids. We recently discovered, in the liver, that the regulatory enzymes that control BCAA metabolism in the mitochondria also regulate a cytosolic enzyme that coordinates glucose and lipid metabolism. It is unknown whether this new metabolic regulatory node has a role in HF. The overall objective of this application is to determine the role of dysregulated systemic and cardiac-specific BCAA metabolism in structural and metabolic remodeling in HF.
Our specific aims are (1) To determine how dysregulation of hepatic and cardiac BCAA metabolism during HF contributes to HF pathogenesis and (2) To determine if the regulatory system of cardiac BCAA metabolism also influences fuel preference in the failing heart. To achieve Aim 1, we will generate liver- and heart-specific knockout mice that promote hepatic or cardiac BCAA catabolism, respectively. We will then induce HF in these animals and will characterize the functional and molecular changes in the heart to determine how organ-specific alterations in BCAA metabolism affect HF progression. To achieve Aim 2, we will use state-of-the art metabolic flux techniques in isolated beating hearts from these animals to determine how the genetic manipulations affect cardiac fuel use. If successful, these studies will define new mechanistic bases for structural and metabolic remodeling in the failing heart. Together, these experiments will allow me to build on the following skills: 1) basic biochemical, molecular and metabolic research techniques; 2) generation and utilization of animal models of cardiac disease; and 3) cardiac metabolic and physiological phenotyping. The data gathered during this award period coupled with mentorship from leaders in the fields of basic and translational metabolism research will prepare me to fulfill my long-term goal of becoming an independent physician-scientist in the field of cardiometabolic disease.
Using the varied approaches in this project, we will clarify the role of a newly discovered cardiac metabolic pathway in mediating abnormal growth and metabolism during heart failure, which will add to our basic understanding of how the heart fails. In addition, if altering this pathway slows or reverses heart failure, as we hypothesize, then drugs targeting the pathway could improve the lives of the millions of people worldwide suffering from this crippling disease.
| McGarrah, Robert W; Crown, Scott B; Zhang, Guo-Fang et al. (2018) Cardiovascular Metabolomics. Circ Res 122:1238-1258 |
