Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia

Departments of 1 Physiology, 2 Department of Pediatrics-Diabetes Research, and 3 Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky; 4 Department of Biochemistry, Molecular Biology, and Biophysics, Medical School, University of Minnesota, Minneapolis, Minnesota; and 5 Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, Kentucky Submitted 20 December 2007 ; accepted in final form 28 April 2008 During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P 2 ), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P 2 . Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart. glycolysis; transgenic Address for reprint requests and other correspondence: P. N. Epstein, Dept. of Pediatrics-Diabetes Research, Univ. of Louisville School of Medicine, 570 S. Preston St., Baxter Biomedical Bldg., Suite 304, Louisville, KY 40202 (e-mail: paul.epstein{at}louisville.edu )