title: Lack of myoglobin causes a switch in cardiac substrate selection.
abstract: 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 beta-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 utilization, the observed shift in substrate metabolism 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.
authors.affiliation: Institut für Herz-und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, Germany. floegel@uni-duesseldorf.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flögel
authors.forename: Tim
authors.initials: T
authors.lastname: Laussmann
authors.forename: Axel
authors.initials: A
authors.lastname: Gödecke
authors.forename: Nadine
authors.initials: N
authors.lastname: Abanador
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Christian Dominik
authors.initials: CD
authors.lastname: Fingas
authors.forename: Sabine
authors.initials: S
authors.lastname: Metzger
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Christoph
authors.initials: C
authors.lastname: Jacoby
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schrader
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D009124:Muscle Proteins / Q000032:analysis; D009206:Myocardium / Q000378:metabolism*; D009211:Myoglobin / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000032:analysis; D019308:Palmitic Acid / Q000378:metabolism; D049268:Positron-Emission Tomography; D020543:Proteome
chemical_list: D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009211:Myoglobin; D047493:PPAR alpha; D020543:Proteome; C495693:Slc2a4 protein, mouse; D019308:Palmitic Acid; D009569:Nitric Oxide; D005947:Glucose