Abstract
Mice lacking myoglobin survive to adulthood and meet the circulatory demands of exercise and pregnancy without cardiac decompensation. In the present study, we show that many myoglobin-deficient embryos die in utero at midgestation with signs of cardiac failure. Fetal mice that survive to gestational day 12.5, however, suffer no subsequent excess mortality. Survival in the absence of myoglobin is associated with increased vascularity and the induction of genes encoding the hypoxia-inducible transcription factors 1alpha and 2, stress proteins such as heat shock protein 27, and vascular endothelial growth factor. These adaptations are evident in late fetal life, persist into adulthood, and are sufficient to maintain normal myocardial oxygen consumption during stressed conditions. These data reveal that myoglobin is necessary to support cardiac function during development, but adaptive responses evoked in some animals can fully compensate for the defect in cellular oxygen transport resulting from the loss of myoglobin.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptation, Physiological / genetics
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Adaptation, Physiological / physiology*
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Blood Vessels / abnormalities
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Blood Vessels / pathology
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Cardiomegaly / chemically induced
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Cardiomegaly / genetics
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Cardiomegaly / pathology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Embryo Loss / etiology
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Embryo Loss / genetics
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Embryo Loss / metabolism*
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Embryo Loss / pathology
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Embryo, Mammalian / pathology
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics
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Female
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Gene Expression Regulation, Developmental
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Heart Failure / complications
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Heart Failure / genetics
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Heart Failure / metabolism*
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Heart Failure / pathology
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Heat-Shock Proteins / biosynthesis
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Heat-Shock Proteins / genetics
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Heterozygote
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Homozygote
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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In Vitro Techniques
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Lymphokines / biosynthesis
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Lymphokines / genetics
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Male
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Mice
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Mice, Knockout
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Myocardial Ischemia / genetics
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Myocardial Ischemia / pathology
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Myocardium / metabolism*
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Myocardium / pathology
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Myoglobin / deficiency*
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Myoglobin / genetics
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Myoglobin / metabolism
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Oxygen Consumption / genetics
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Phenotype
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Survival Rate
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Transcription Factors*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Endothelial Growth Factors
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Heat-Shock Proteins
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lymphokines
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Myoglobin
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Nuclear Proteins
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Trans-Activators
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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endothelial PAS domain-containing protein 1