Published online before print April 7, 2005, doi: 10.1161/01.RES.0000165481.36288.d2
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Submitted on May 11, 2004
Revised on March 24, 2005
Accepted on March 28, 2005
Lack of Myoglobin Causes a Switch in Cardiac Substrate Selection
Ulrich Flögel *;
From the Institut für Herz-und Kreislaufphysiologie (U.F., T.L., A.G., N.A., C.D.F., C.J., J.S.), Heinrich-Heine-Universität Düsseldorf; Klinik und Poliklinik für Nuklearmedizin (M.S.), Universitätsklinikum Münster; Biomedizinisches Forschungszentrum (S.M.), Heinrich-Heine-Universität Düsseldorf; and Institut für Arterioskleroseforschung (B.L.), Universität Münster, Germany.
* To whom correspondence should be addressed. E-mail: floegel{at}uni-duesseldorf.de.
Myoglobin is an important intracellular O2 binding hemoprotein in heart and skeletal muscle. Surprisingly, disruption of myoglobin in mice (myo-/-) resulted in no obvious phenotype and normal cardiac function was suggested to be mediated by structural alterations that tend to steepen the oxygen pressure gradient from capillary to mitochondria. Here we report that lack of myoglobin causes a biochemical shift in cardiac substrate utilization from fatty acid to glucose oxidation. Proteome and gene expression analysis uncovered key enzymes of mitochondrial 
-oxidation as well as the nuclear receptor PPAR
to be downregulated in myoglobin-deficient hearts. Using FDG-PET we showed a substantially increased in vivo cardiac uptake of glucose in myo-/- mice (6.7±2.3 versus 0.8±0.5% of injected dose in wild-type, n=5, P<0.001), which was associated with an upregulation of the glucose transporter GLUT4. The metabolic switch was confirmed by 13C NMR spetroscopic isotopomer studies of isolated hearts which revealed that [1,6-13C2]glucose utilization was increased in myo-/- hearts (38±8% versus 22±5% in wild-type, n=6, P<0.05), and concomitantly, [U-13C16]palmitate utilization was decreased in the myoglobin-deficient group (42±6% versus 63±11% in wild-type, n=6, P<0.05). Because of the O2-sparing effect of glucose, the observed shift in substrate utilization benefits energy homoeostasis and therefore represents a molecular adaptation process allowing to compensate for lack of the cytosolic oxygen carrier myoglobin. Furthermore, our data suggest that an altered myoglobin level itself may be a critical determinant for substrate selection in the heart. The full text of this article is available online at http://circres.ahajournals.org.
Key words: metabolism •
-oxidation •
glucose •
oxygen •
heart
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