Molecular Characterization of Extraocular Muscle

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DESCRIPTION (provided by applicant): The extraocular muscles (EOM) are highly specialized muscles that affect a wide range of motions from the slow vestibulo-ocular reflexes to the rapid saccadic movements. The demands on them are constant, and the responses must be precise. Because the demands on these muscles are distinct from those on other skeletal muscles, it is not surprising that the detailed properties of EOMs are different from those of other muscles. What is surprising - and most important - is that the EOMs have differential sensitivity to certain diseases. EOMs have an increased involvement in disorders such as myasthenia gravis, Grave's disease and mitochondrial myopathies. Enigmatically, they are spared in Duchenne muscular dystrophy, despite the widespread involvement of all other skeletal muscle groups. While it is currently unclear why EOM are selectively involved or spared in different diseases, it has been hypothesized that EOM are a unique set of skeletal muscles and that their 'group-specific' properties play a role in their unique patho-physiology. Consistent with this hypothesis, certain genes (e.g. EOM-specific myosin, certain ACHR subunits) are differentially expressed in EOM compared to other skeletal muscles. This has been confirmed in our laboratory by gene expression profiling comparing EOMs and limb muscles over a small part of the transcriptome. Our central thesis is that EOMs are fundamentally different from other skeletal muscles in their gene expression profile; and that we can trace their unique properties and disease susceptibilities to specific and unique patterns of gene expression. To test these hypotheses we propose: (a) to use gene expression profiling to extend the comparison between EOMs and limb muscles to the entire transcriptome; i.e. beyond the one-third that we have already finished; (b) to use a variety of immunological, molecular, and biochemical methods to validate results of expression profiling and resolve inadequacies and disparities among previous studies; (c) to examine the ability of satellite cells to maintain growth and regeneration in normal mice, in mdx mice, in mdx mice treated with anti myostatin, and in mdx/MyoD knockout mice. This latter set of experiments should validate a major discovery from our previous profiling: that increased regenerative potential is a source of EOM resistance to DMD.