Abstract
Previous studies have indicated that myoblasts can differentiate and repair muscle injury after an ischemic insult. However, it is unclear how hypoxia or glucose deprivation in the ischemic microenvironment affects myoblast differentiation. We have found that myogenesis can adapt to hypoxic conditions. This adaptive mechanism is accompanied by initial inhibition of the myoD, E2A, and myogenin genes followed by resumption of their expression in an oxygen-dependent manner. The regulation of myoD transcription by hypoxia is correlated with transient deacetylation of histones associated with the myoD promoter. It is noteworthy that, unlike the differentiation of other cell types such as preadipocytes or chondroblasts, the effect of hypoxia on myogenesis is independent of HIF-1, a ubiquitous regulator of transcription under hypoxia. While myogenesis can also adapt to glucose deprivation, the combination of severe hypoxia and glucose deprivation found in an ischemic environment results in pronounced loss of myoblasts. Our studies indicate that the ischemic muscle can be repaired via the adaptive differentiation of myogenic precursors, which depends on the levels of oxygen and glucose in the ischemic microenvironment.
MeSH terms
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Acetylation
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Adaptation, Physiological*
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Cell Differentiation
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Cell Hypoxia
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Cell Line
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Down-Regulation
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Energy Metabolism / genetics
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Energy Metabolism / physiology
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Gene Expression Regulation, Developmental
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Glucose / metabolism
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Histones / metabolism
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mice
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Muscle Development / genetics
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Muscle Development / physiology*
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MyoD Protein / genetics
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MyoD Protein / metabolism*
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Myoblasts / metabolism*
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Myogenin / genetics
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Myogenin / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology
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Oxygen / metabolism
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Oxygen / pharmacology
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / genetics
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RNA Stability
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RNA, Messenger / analysis
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RNA, Messenger / metabolism
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Sequence Deletion
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology
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Transcription, Genetic
Substances
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Hif1a protein, mouse
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Histones
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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MyoD Protein
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Myog protein, mouse
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Myogenin
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Nuclear Proteins
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RNA, Messenger
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Tcf3 protein, mouse
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Transcription Factors
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Glucose
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Oxygen