DETERMINANTS OF EXTRAOCULAR MUSCLE FUNCTION

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DESCRIPTION (Adapted from Applicant's abstract): The extraocular muscles (EOMs) are not typical skeletal muscles. Their anatomical arrangement and fiber type heterogeneity are suggestive of functional versatility, and their contractile properties present characteristics not commonly seen in other skeletal muscles. A feature of EOMs is the presence of two fiber layers: orbital, closer to the orbit; and global, closer to the eyeball. Each layer has a particular population of fiber types and may have a specific role in eye movement. In addition, EOMs have the highest mitochondrial content of all mammalian skeletal muscles, probably as a consequence of their almost constant activity. However, we know more about the structural traits of the EOMS than we do about how these translate into the functional properties of this muscle group. The functional differences between the orbital and global layers, and the role of mitochondria in the instantaneous regulation of free cystolic Ca 2+ of EOMs have not yet been explored. The central hypothesis of this project proposes that EOM function depends on the compartmentalization of distinct Ca2+handling properties to discrete muscle layers and the use of mitochondria as novel cytosolic Ca2+ sinks. This hypothesis will be tested with experiments combining in vitro physiological and pharmacological studies with the use of Ca2+-specific fluorescence spectroscopy. To establish the functional limits of EOMs and those cellular elements that determine them, we will (1) examining the Ca2+ handling ability of global and orbital layers of EOM; (2) analyze the Ca2+ kinetics of identified EOM fibers; and (3) determine the functional consequences of abnormal EOM development. The proposed experiments are an initial approach to establishing the cellular elements that determine the functional properties of EOMs. First, available evidence suggests that the functional properties of the two EOM layers are different. Second, rapid Ca2+ handling by the EOMs may include the novel use of mitochondria as alternative Ca2+ sinks. Third, abnormal visual development and disrupted EOM-specific myosin expression may alter the contractile of Ca2+ handling characteristics of EOMs. The results from this project will increase our understanding of the physiology of EOMs, and provide insights into the behavior of this muscle group in disorders such as strabismus, and their response to therapeutic interventions.