Molecular and Cellular Control of Muscle Cell Phenotype
Much of our research focuses on the mechanisms that establish and maintain skeletal muscle fiber type diversity during development. Research in our lab is based on avian model systems in which both intrinsic and extrinsic regulation of muscle fiber type is analyzed. Unique muscle cell/nerve co-cultures are generated to explore the cell-cell interactions leading to muscle cell diversity. Direct electrical stimulation of muscle fibers in vitro is also being employed in our studies. Our research indicates that intrinsic differences between myoblasts before overt differentiation leads to diversity in muscle fiber types. Additionally, innervation modulates muscle fiber type and associated fiber type specific gene expression. Published results indicate that protein kinase C (PKC) activity in conjunction with innervation-induced activation of cell signaling mediated by the muscarinic acetylcholine receptor, Gaq, and the 1,4,5 inositol triphosphate receptor 1 (IP3R1) differentially regulate fast versus slow muscle fiber type gene expression in innervated muscle fibers. This signaling culminates in regulation of transcription factors governing expression of the slow myosin heavy chain 2 gene - indicative of the slow muscle fiber phenotype. Our on-going research is focused on the regulatory mechanisms that link innervation, PKC activity, IP3R1 activity, transcriptional regulators, and expression of slow muscle fiber type specific genes.
More recently, we have initiated studies to investigate the molecular mechanisms that control the development of distinct myogenic cell lineages during embryonic mygenesis. These lineages are defined are distinct types of embryonic myoblasts that are committed to the differentiation of diverse, lineage-based, muscle fiber types types. The aim of this research is to identify and characterize the molecular regulatory circuitry that establishes these myogenic cell lineages and which thereby establish fast versus fast/slow muscle fiber types, independent of innervation, and dependent of cell lineage commitment.