Identification of underlying mechanisms by which increased fatty acid utilization impairs mitochondrial functionin the heart

• Applicant: Professor Dr. Heiko Bugger
• Subject Area: Cardiology, Angiology
• Term: from 2007 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 46117609

Type 2 diabetes increases the risk for the development of non-ischemic heart failure. Recent evidence suggests an important role of increased cardiac fatty acid (FA) utilization. For example, db/db mice, a model of type 2 diabetes, show contractile dysfunction, associated with increased FA utilization. However, underlying mechanisms by which increased FA utilization may induce contractile dysfunction remain to be fully elucidated. We recently identified mitochondrial respiratory dysfunction and alterations in mitochondrial morphology in db/db mouse hearts. Mitochondrial dysfunction is thought to contribute to diabetic complications. These results raise the possibility that increased FA utilization in the diabetic heart may cause mitochondrial dysfunction, leading to energy depletion and contractile dysfunction. Indeed, preliminary experiments in a mouse model with a selective increase in cardiomyocyte FA utilization also revealed contractile dysfunction, mitochondrial dysfunction, and alterations in mitochondrial morphology, similar to the changes in db/db mice. However, how increased FA utilization leads to mitochondrial dysfunction is unknown. Therefore, we propose to investigate mechanisms and signaling pathways by which increased cardiac FA utilization may impair mitochondrial function, using mice with cardiomyocyte-selective increase in FA uptake. These studies will provide new mechanistic insights into the pathogenesis of contractile dysfunction in diabetes and may provide a rationale for modulating myocardial FA utilization as a therapeutic strategy.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor E. Dale Abel, Ph.D.