Grant: Foundation Grant

The very high energy demands of the heart are met by continous metabolism of sugars, fatty acids, ketones and amino acids. Normally, there is a balance between the use of these fuels. However, in clinical conditions such as heart failure, myocardial ischemia (i.e. such as following a heart attack), obesity or diabetes, energy production in the heart switches towards an excessive use of fatty acids. This excessive use of fatty acids causes the heart to be less efficient at using energy, which can compromise heart function. Our research has shown that a major contributor to this excessive use of fatty acids is due to changes in the levels of a molecule called malonyl CoA within the heart muscle, and due to an increase in a process caused post-translational acetylation. The studies proposed in this grant application will determine the cellular mechanisms responsible for how malonyl CoA levels and acetylation are regulated in the heart, and how alterations in these processes alters fatty acid use by the heart. We will also determine if preventing the switch from sugar to fatty acid metabolism, can be used as a therapeutic strategy to protect the heart in heart failure or following myocardial ischemia. We will also examine the molecular mechanisms responsible for the maturation of cardiac fatty acid oxidation following birth, and what impact congenital heart defects (that are seen in approximately 2% of infants) has on this maturation of energy metabolism. These experimental studies will be translated into clinical studies in which energy metabolism is optimized to improve heart function in patients with heart failure. Understanding how energy metabolism is regulated in heart should lead to the development of therapies that optimize energy use by the heart and decrease the severity of heart disease.