1. ¹Department of Pathology, University of Graz, Graz, Austria
2. ²Department of Pharmacology and Toxicology, University of Graz, Graz, Austria
3. ³Department of Medical Biochemistry, University of Graz, Graz, Austria
4. ⁴Department of Molecular Biology, Biochemistry and Microbiology, University of Graz, Graz, Austria
5. ⁵Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence: Dr. G. Hoefler, Department of Pathology, University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria. E-mail: gerald.hoefler@uni-graz.at

Received 11 October 2002.

Abstract

Free fatty acids (FFA) are liberated from triglyceride-rich lipoproteins by lipoprotein lipase (LPL) and are considered to be a principal energy source for the heart. The peroxisome proliferator-activated receptor alpha (PPAR) is a key regulator of FFA catabolism. To investigate its role in cardiac muscle metabolism, transgenic mice overexpressing LPL in skeletal and cardiac muscle were bred on a PPAR knockout background. Fifty-five percent of male animals lacking PPAR and overexpressing LPL died within 4 months after birth. In contrast, females of this genotype stayed alive. Deceased animals exhibited cardiopulmonary congestion but had no increase of neutral lipids in the heart. Changes in plasma glucose, FFA, lactate, and triglycerides did not clearly account for gender-specific differences in mortality; however, they indicated a critical role for PPAR during fasting. Analysis of cardiac function revealed that in isolated perfused hearts, left ventricular developed pressure (a measure of contractility) was markedly lower in PPAR knockout mice overexpressing LPL compared with controls. Glucose uptake of isolated perfused hearts was significantly higher in PPAR knockout mice with both normal or increased LPL expression. However, uptake of FFA was not different among genotypes. In contrast, fasted FFA levels were significantly lower in cardiac muscle of PPAR knockout mice with normal LPL expression (-26%) and PPAR knockout mice overexpressing LPL (-38%) compared with controls. Our results indicate a critical role for PPAR in myocardial pump function and suggest that mouse models combining different genetic effects such as PPAR knockout mice overexpressing muscle LPL may be useful to study cardiomyopathies.