Striated muscles of vertebrate organisms differ markedly in their biochemical, ultrastructural, and physiological characteristics, reflecting adaptations to varying work demands. The overall goal of this proposal is to understand the molecular mechanisms responsible for development, maintenance, and activity-dependent interconversion of these highly specialized muscle subtypes. Preliminary studies have focused on the human myoglobin gene as a model for the class of genes that are activated during muscle differentiation, but subject to important regulation during maturation of specialized glycolytic and oxidative skeletal fibers, and in response to changes in neural input and muscle activity. We propose to extend these studies to accomplish three specific aims: (1) We need to achieve a more detailed understanding of the myoglobin muscle-specific enhancer and its function during muscle differentiation with respect to several questions. What is the relative importance of positive and negative control elements within the enhancer for establishing and maintaining the differentiated phenotype? What is the identity of proteins that bind these elements and their relationship to the products of known myogenic determination genes? What is the basis for the requirement for specific TATA sequences for enhancer function? (2) We propose to define cis-acting control elements and cognate binding factors responsible for differential expression of the myoglobin gene after maturation of specialized muscle subtypes of adult animals. Do variations in myoglobin gene transcription in specialized subtypes of striated muscle result from direct modulation of factors responsible for gene activation during myogenesis, or from distinct and separate regulatory events? (3) We propose to define genetic mechanisms that modulate myoglobin gene transcription as an adaptive response to variations in neural input and contractile activity in the adult animal. Do physiological stimuli modulate gene expression through the same control elements and by inducing quantitative or qualitative changes in cognate binding factors important during myogenesis and maturation of specialized muscle subtypes, or are different regulatory pathways involved? Are unique regulatory genes expressed in response to neural stimulation that drive interconversion of muscle subtypes? Our ability to achieve these aims not only will increase understanding of the mechanisms of action of myogenic determination genes, but the distinctive focus on maturation and interconversion of specialized muscle subtypes in adult animals offers prospects for unique findings with potential clinical relevance.
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