Myogenic Cell Lineages and Muscle Fiber Type Formation

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DESCRIPTION (provided by applicant): Vertebrate skeletal muscle fibers originate from myoblast precursor cells that appear at multiple times during development. These muscle fibers display diversity in expression of contractile and metabolic genes that establish and maintain phenotypic diversity in contraction speed and metabolic capacity. The plasticity of muscle fibers with regard to their response to extrinsic signals such as innervations largely determines their fast versus slow muscle fiber type identity. This prevailing notion is based mostly on the large number of studies of fetal (secondary) muscle fibers. However, very few studies have focused on the mechanisms that regulate muscle fiber type formation during primary myogenesis. These fibers form initially in the absence of functional innervations and yet display diversity in expression of myosin heavy chain (MyHC) genes and muscle fiber type. This diversity is grounded in the commitment of distinct myoblast cell lineages to the formation of these fast and fast/slow primary muscle fibers. The mechanisms that regulate the development of fast and fast/slow primary muscle fibers from these distinct myoblast cell lineages are completely unknown since no appropriate vertebrate model system has been available for their investigation. This research proposal presents such a model system and reports preliminary studies that establish the rationale and feasibility for investigation of the mechanism that controls myoblast cell lineage commitment to distinct muscle fiber type formation. The central hypothesis to be addressed by the specific aims is: Development of different primary muscle fiber types is regulated by cell autonomous, lineage-specific mechanisms mediated by the transcription factors LHX9 and a small cohort of transcriptional co-regulators that activate the slow MyHC2 promoter. The specific aims for the research are: 1. Identification and characterization of the transcriptional complex that activates the slow MyHC2 gene promoter in the fast/slow versus fast myogenic cell lineage, 2. Determine the role of the LIM homeodomain transcription factor, LHX9, in cell lineage-dependent muscle fiber type specification, and 3. Identification of LHX9 protein-protein interactions that regulate slow MyHC2 gene expression. These studies will provide important insight into the molecular and cellular regulation of muscle phenotype during development and regeneration from disease states. PUBLIC HEALTH RELEVANCE: Vertebrate skeletal muscle fibers originate from myoblast precursor cells that appear at multiple times during development. These muscle fibers display diversity in expression of contractile and metabolic genes that establish and maintain phenotypic diversity in contraction speed and metabolic capacity. These studies will provide important insight into the molecular and cellular regulation of muscle phenotype during development and regeneration from disease states.