Thyroid dysfunction affects some 10 million Americans; and although the extraocular muscles (EOMs) are often involved in thyroid disease, little is known about the effects of T3 on the properties or development of EOM fibers. The effects of dysthyroidisms on the function of appendicular muscle fibers suggest that altered T3 levels should have profound influences on the performance of EOM fibers; however, there unique developmental origin, structural and functional properties and singular reactions to diseases suggest that EOMs have unique rules governing gene expression. T3 regulates the contractile properties of muscle fibers by differentially activating or repressing isoforms of the myosin heavy chains (MyHCs). The transcriptional control is mediated by the thyroid receptors (TRs) and the retinoid X receptors (RXRs) which themselves exist as multiple isoforms. Preliminary data, as well as susceptibilities to disease, suggest that the response of genes to T3 in EOMs will differ from that in other muscles. We hypothesize this differential response will be related to unusual distributions of TR and RXR isoforms among fibers; altered T3 levels will lead to the expression of inappropriate MyHC isoforms, abnormal contractile characteristics and impaired vision. Proving this hypothesis requires (a) determining which MyHC genes are expressed in each EOM fiber type during development and in the adult, (b) correlating the MyHC complement of each fiber to the contractile properties of that fiber, (c) determining whether hypo-and hyperthyroidism after the expression of MyHC genes and contractile properties, (d) discriminating the TR and RXR isoforms synthesized in euthyroid and pathological conditions. Studies will isoform-specific cRNA probes and antibodies will be combined with contractile measurements of individual skinned EOM fibers to accomplish these aims. To understand how the eye performs its repertoire of motions under both normal and pathological circumstances, one must understand the synthetic capacity of each fiber and how it defines the functional properties of each fiber.
