Determinants of extraocular muscle function

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DESCRIPTION (provided by applicant): Congenital strabismus, or eye misalignment, affects about 4% of children. However, available therapies are not yet optimal, with significance incidence of recurrence or unsatisfactory functional results. The extraocular muscles, the final effector arm of the oculomotor system, are the target of surgical and pharmacological treatments for strabismus. This is despite the fact that our understanding of extraocular muscle biology and function remains incomplete. Although the extraocular muscles are included in the skeletal muscle class, there is emerging evidence that basic metabolic and functional characteristics of these small muscles are significantly different from those seen in typical skeletal muscles. First, mitochondria serve as novel fast calcium sinks in extraocular muscles, and this mechanism is an important determinant of the functional characteristics of these muscles. Second, abnormal visual experience during a postnatal critical period significantly alters the extraocular muscles, and renders them weaker, slower and more fatigable. Third, the gene expression profile of the extraocular muscles is greatly different from that of other skeletal muscles. These data suggest that the divergent functional properties of the extraocular muscles must be met by alternative strategies for energy supply. In consequence, the objective of this project is to understand how metabolic pathways have adapted in the extraocular muscles to cope with their extreme functional requirements. Using well-established functional, molecular biological and biochemical assays, this project will determine (1) the role of alternative energy supply pathways in rat extraocular muscles; (2) the extent to which rat extraocular muscle mitochondria are different; and (3) the role of normal visual experience in establishing these metabolic properties in rat extraocular muscles. It is expected that these experiments will obtain significant new information the overall metabolic characteristics of the extraocular muscles, and provide an integrative view of functional and metabolic properties of these muscles. By understanding what sets the extraocular muscles apart from other skeletal muscles, interventions that directly target these muscles can be envisioned.