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 def iciency on cardiac function by producing myoglobin-knockout (myo(-/-)) mice . To genetically inactivate the myoglobin gene, exon 2 encoding the heme bi nding site was deleted in embryonic stem cells via homologous recombination . Myo(-/-) mice are viable, fertile, and without any obvious signs of funct ional limitations. Hemoglobin concentrations were significantly elevated in myo(-/-) mice. Cardiac function and energetics were analyzed in isolated p erfused hearts under resting conditions and during beta-adrenergic stimulat ion with dobutamine. Myo(-/-) hearts showed no alteration in contractile pa rameters either under basal conditions or after maximal beta-adrenergic sti mulation (200 nM dobutamine). Tissue levels of ATP, phosphocreatine (P-31-N MR), and myocardial O-2 consumption were not altered. However, coronary flo w (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) gradi ent and reduce the diffusion path length for O-2 between capillary and the mitochondria; this suggests that myoglobin normally is important for the de livery of oxygen.