Effect of Ketone Bodies on Mitochondrial Cardiomyopathy and Heart Aging
Abstract
The proposed research project addresses the Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area, Mitochondrial Disease. Mitochondrial diseases result from defects in mitochondria, the specific part of a cell where most of the energy is generated. Mitochondrial diseases, which are estimated to affect 1 in 4000 people, can be inherited or acquired, and could affect any individuals including military personnel and their families. Effective therapeutic approaches for mitochondrial diseases have yet to be established. Since mitochondria are the “powerhouse of the cell,” mitochondrial diseases often affect tissues that require a lot of energy, such as the heart, brain, and muscle. Cardiomyopathy affecting the heart muscle is one of such symptoms, which often leads to heart failure. In order to discover and test a strategy to prevent mitochondrial cardiomyopathy and heart failure, animal models showing these symptoms are extremely valuable. We recently identified transmembrane protein 135 (TMEM135), a novel molecule that regulates mitochondrial size, and found that excessive amount of TMEM135 in mice (Tg-Tmem135 mice) causes sudden death at a young age with heart failure and cardiomyopathy. The size of mitochondria is smaller in the heart of these mice compared to normal mice, and mitochondria’s functions are failing. These findings indicate that proper regulation of mitochondrial size is essential for normal heart function. Interestingly, the disease symptoms and the pattern of gene expression in the heart of Tg-Tmem135 mice resemble those of aged mice. Taken together, Tg-Tmem135 mice provide a novel mouse model for cardiomyopathy associated with mitochondrial defects and aging. We found that the metabolism of certain types of essential amino acids, branched chain amino acids (BCAAs), which mainly happens in the mitochondria, are significantly decreased in the heart of Tg-Tmem135 mice. We also found that the lack of one of the BCAAs, leucine, particularly increases stress and causes abnormalities in heart muscle cells. These findings suggest that mitochondrial defects affect the leucine metabolism in the heart resulting in inefficient energy supplies to the heart muscle, which may increase stress to the heart and lead to heart muscle disease in Tg-Tmem135 mice. Similar decrease in BCAA metabolism and energy supply to the heart occur in the course of aging, giving stress to the heart and resulting in cardiomyopathy. Since leucine is metabolized to ketone bodies to be used as the energy source, we hypothesize that decreased metabolism of leucine in the heart of Tg-Tmem135 mice and aged mice may be overcome by supplementation of ketone bodies. In this proposal, we will test this innovative strategy to prevent cardiomyopathy caused by mitochondrial defects and aging by examining the effect of ketone body supplementation to the animal model showing cardiomyopathy caused by mitochondrial defects as well as to aging mice. This supplementation may increase the energy supply to the heart, decrease stress to the heart muscle, prevent the heart muscle disease, and protect heart muscles from aging. Knowledge gained from this study can be applied to develop preventative approaches for heart symptoms in patients with mitochondrial diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710341
Entities
People
- Akihiro Ikeda
Organizations
- United States Army
- University of Wisconsin–Madison