Disruption of myoglobin in mice induces multiple compensatory mechanisms

Myoglobin may serve a variety of functions in muscular oxygen supply, such as O-2 storage, facilitated O-2 diffusion, and myoglobin-mediated oxidative phosphorylation. We studied the functional consequences of a myoglobin deficiency on cardiac function by producing myoglobin-knockout (myo(-/-)) mice. To genetically inactivate the myoglobin gene, exon 2 encoding the heme binding site was deleted in embryonic stem cells via homologous recombination. Myo(-/-) mice are viable, fertile, and without any obvious signs of functional limitations. Hemoglobin concentrations were significantly elevated in myo(-/-) mice. Cardiac function and energetics were analyzed in isolated perfused hearts under resting conditions and during beta-adrenergic stimulation with dobutamine. Myo(-/-) hearts showed no alteration in contractile parameters either under basal conditions or after maximal beta-adrenergic stimulation (200 nM dobutamine). Tissue levels of ATP, phosphocreatine (P-31-NMR), and myocardial O-2 consumption were not altered. However, coronary flow (6.4 +/- 1.3 ml min(-1) g(-1) [wild-type (WT)] vs. 8.5 +/- 2.4 ml min(-1) g(-1) [myo(-/-)]) and coronary reserve [17.1 +/- 2.1 (WT) vs. 20.8 +/- 1.1 (myo(-/-)) ml min(-1) g(-1)]were significantly elevated in myo-/- hearts. Histological examination revealed that capillary density also was increased in myo-/- hearts [3,111 +/- 400 mm(-2) (WT) vs. 4,140 +/- 140 mm(-2) (Myo(-/-))]. These data demonstrate that disruption of myoglobin results in the activation of multiple compensatory mechanisms that steepen the pO(2) gradient and reduce the diffusion path length for O-2 between capillary and the mitochondria; this suggests that myoglobin normally is important for the delivery of oxygen.