Extraocular muscles (EOM) are spared or preferentially involved in various skeletal muscle diseases. We propose a novel and controversial alternative mechanism that may form the basis for the differences between extraocular muscles and limb skeletal muscles. We have strong preliminary evidence to suggest that there is ongoing, continuous myofiber remodeling in the adult extraocular muscles. This would involve both myogenic and apoptotic components. These conclusions are based on 4 lines of evidence. In this proposal we are asking questions to confirm our original observations. We have shown that the EOM continue to express cells positive for myogenic regulatory factors, such as myoD. Activated satellite cells are always present in adult EOM. BrdU labeling experiments using both 2 week and 4 week continuous labeling protocols followed by various brdU-free periods, a protocol that labels dividing cells, demonstrated mature myofibers with brdU-positive nuclei within them. Our working hypothesis is that there are mechanisms present in adult EOM that allow continuous satellite cell activation and division, resulting in either continuous remodeling of existing myofibers by fusion of new myoblasts with existing adult myofibers or formation of entirely new myofibers by the fusion of myoblasts with each other. This proposal asks the following questions: What are the mechanisms of myofiber remodeling in adult EOM? What is the time course and extent of fiber remodeling? What role does apoptosis play in myofiber remodeling and by what mechanism? How do surgical and chemodenervation manipulations simulating strabismus treatments cause changes in myofiber remodeling that may be affecting long-term surgical outcomes? The ability of adult EOM to continuously remodel provides a wealth of testable hypotheses for some long-standing enigmas involving the EOM and their preferential sparing or involvement in various muscle diseases. Ultimately, we hope to use this information to develop new therapeutic strategies.for the treatment of strabismus and other ocular and non-ocular muscle diseases.
