Extraocular muscle (EOM) is specifically tailored to serve a diverse repertoire of eye movement control systems. Many aspects of the molecular biology, cell biology, morphology, and function of EOM are very different from the well-describe skeletal muscles of the limb and axial skeleton. Genotype and/or phenoptypic differences in the EOMs may either predispose or protect them in disease. Thus, knowledge of EOM biology is critical in design of theoretical and practical models of eye movements and in preventing or treating disorders. of eye alignment or movement. We currently have almost no knowledge of the cell/molecular substrate for stabilizing the EOM membrane, or sarcolemma, and for formation and maintenance of specializations at the neuromuscular function. What we do know strongly suggests that the transmembrane protein complex that plays these roles in skeletal muscle may exhibit adaptations in EOM. We propose to test the hypothesis that the unique phenotype, and functional properties, of EOM require muscle group-specific adaptations at the level of the intricate complex of proteins that spans the sarcolemma to stabilize during muscle contraction and to organize the neuromuscular junction. First, we will determine the spatial/temporal relationships in maturation EOM and visuomotor systems. Data will establish similarities and differences between EOM and the pattern that has been well described in other muscles. Second, we will investigate the regulatory mechanisms for the specializations in the transmembrane protein complex at neuromuscular junctions in EOM. These studies will allow use to identify the extent to which EOM utilizes general muscle regulatory mechanisms and identify any protein complex in EOM using natural mutant and gene knockout models that generate loss of function in most muscles. Our pilot data establish that EOM responds to loss of components of the transmembrane protein system in ways that other skeletal muscles do not. Proposed studies will begin to understand the molecular mechanisms used by EOM in sarcolemmal organization for the day-to-day function of these novel muscles. An overall knowledge of the properties and regulation of the EOM sarcolemma will be important for understanding and treating ocular motility disorders in myasthenia gravis, congenital fibrosis of EOM, and strabismus.
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