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Myoglobin is an important intracellular O 2 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 β-oxidation as well as the nuclear receptor PPARα 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 13 C NMR spetroscopic isotopomer studies of isolated hearts which revealed that [1,6- 13 C 2 ]glucose utilization was increased in myo −/− hearts (38±8% versus 22±5% in wild-type, n=6, P 13 C 16 ]palmitate utilization was decreased in the myoglobin-deficient group (42±6% versus 63±11% in wild-type, n=6, P 2 -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.