Abstract
Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Cardiomyopathies / diet therapy*
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Cardiomyopathies / genetics
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Cardiomyopathies / metabolism
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Diet, Ketogenic*
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Electrophoresis, Polyacrylamide Gel
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Female
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Gene Expression
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Genes, Lethal
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Kaplan-Meier Estimate
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Male
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Mediator Complex / genetics*
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Mediator Complex / metabolism
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Microscopy, Electron
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Mitochondria, Heart / metabolism
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Mitochondria, Heart / ultrastructure
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Mitochondrial Myopathies / diet therapy*
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Mitochondrial Myopathies / genetics
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Mitochondrial Myopathies / metabolism
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Mutation, Missense*
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Myocardium / metabolism
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Myocardium / pathology
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Amino Acid
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Sequence Homology, Nucleic Acid
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Weaning
Substances
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Med30 protein, mouse
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Mediator Complex
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Protein Subunits