Understanding Mechanisms of Heart Metabolism and Function

Bridging clinical cardiology and research on cellular energy changes

Technology Overview

Dr. Aaron OlsonThe heart uses more energy, by weight, than any other organ. Cardiac energy needs to change in response to stress or disease. Dr. Olson studies how heart cells recognize and respond to fluctuating metabolic demands and how these responses affect heart function. His research is widely applicable, because all organs must monitor their energy status for growth, development, and maintenance.

Dr. Olson studies a mechanism that cells use to link their metabolic state to cellular functions: attachment of O-linked N-acetylglucosamine (O-GlcNAc) to proteins. This modification, which is similar to post-translational protein phosphorylation, is essential. In mice, knocking out the enzyme that adds O-GlcNAc to proteins leads to embryonic lethality. O-GlcNAc is connected to cellular pathways involving sugars, fats, amino acids, and other metabolites, so it could act as a general gauge of metabolic status.

Dr. Olson's group has identified proteins that are modified by O-GlcNAc in cardiac cells, and these proteins may be potential drug targets for heart conditions. This research also has broader applicability, since changes in O-GlcNAc are associated with cancer, diabetes, and neurodegeneration including Alzheimer's disease. Dr. Olson's group published results suggesting that the protooncogene c-Myc, which is involved in cancer development, regulates cardiac hypertrophy, or abnormal enlargement of the heart, by influencing O-GlcNAc modification of proteins.

In addition to basic biochemical methods, Dr. Olson's group has expertise in surgically generating mouse models of heart conditions such as aortic stenosis (narrowing of the aortic valve). Dr. Olson also has expertise in the ex vivo isolated working heart perfusion technique to study cardiac metabolism or acute drug effects. They are experienced in working with mouse models for other conditions that affect the heart such as high blood pressure. As a cardiologist, Dr. Olson can advise on how to improve the clinical relevance of research on heart disease using model organisms.

Stage of Development

• Preclinical in vivo
• Preclinical ex vivo

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement

Publications

1. Standage SW, Bennion BG, Knowles TO, Ledee DR, Portman MA, McGuire JK, Liles WC, Olson, AK. PPARα augments heart function and cardiac fatty acid oxidation in early experimental polymicrobial sepsis. Am J Physiol-Heart and Circ Physiol. 2017;312(2): H239–H249. 
2. Ledee D, Smith L, Bruce M, Kajimoto M, Isern N, Portman MA, Olson AK. C-Myc alters substrate utilization and O-GlcNAc protein posttranslational modifications without altering cardiac function during early aortic constriction. PLoS One. 2015;10(8):e0135262.
3. Ledee D, Portman MA, Kajimoto M, Isern N, Olson AK. Thyroid hormone reverses aging-induced myocardial fatty acid oxidation defects and improves the response to acutely increased afterload. PLoS ONE. 2013;8(6): e65532. 
4. Olson AK, Ledee D, Iwamoto K, Kajimoto, M, O'Kelly Priddy C, Isern N, Portman MA. C-Myc induced compensated cardiac hypertrophy increases free fatty acid utilization for the citric acid cycle. J Mol Cell Cardio. 2013;55:156–164.

Learn More

• Aaron Olson, MD