Ca Sparks in Muscle Aging and Dystrophy

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DESCRIPTION (provided by applicant): Ca sparks are the elementary units of Ca-induced Ca release (CICR) in striated muscle cells revealed as localized Ca release events from sarcoplasmic reticulum (SR) by confocal microscopy. While Ca sparks are well defined in cardiac muscle, there has been a general belief that these localized Ca release events are rare in intact adult mammalian skeletal muscle. As a result of the intrinsic difficulties in monitoring Ca spark activity in intact mammalian muscle, the cellular and molecular mechanisms underlying the regulation of CICR in muscle function and the adaptive changes of CICR in muscle aging and dystrophy remain largely unexplored. Recently, we discovered that stress generated by membrane deformation induces a robust Ca spark response spatially confined in close proximity to the sarcolemmal membrane in healthy young mammalian muscles. These induced Ca sparks are repeatable and reversible in young muscle fibers, but become transient and static in aged skeletal muscle. In dystrophic muscle with fragile membrane integrity, induced Ca sparks are irreversible and penetrate from the periphery to the fiber interior. Thus, uncontrolled Ca spark activity could potentially lead to partial depletion of the SR Ca store, triggering increased store- operated Ca entry (SOCE) and providing a dystrophic signal in mammalian skeletal muscle. We hypothesize that Ca sparks can be used as a measure of the plastic nature of CICR in muscle health, aging and dystrophy. Experiments proposed in this project shall focus on addressing the following fundamental questions regarding the physiological function of Ca sparks in skeletal muscle: First, what are the cellular factors that are responsible for the peripheral distribution and the plasticity of Ca sparks in young, healthy skeletal muscle? Second, is there dynamic bi-directional coupling between Ca sparks and SOCE, and does alteration of this coupling produce muscle dysfunction? Third, how do triad-junction resident proteins influence Ca spark function in health, aging and disease? As defects in control of CICR have been linked to numerous pathologic states, including heart failure and neurodegenerative conditions, we hope knowledge gained from our studies will not only help establish the physiological function of stress-induced Ca sparks in skeletal muscle fibers, they may also point to potential therapeutic targets in excitable cells where dysfunction of CICR has been observed.