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School of Physics Soft Condensed Matter and Biophysics Seminar: Presenting Jon Lederer, University of Maryland School of Medicine
X-ROS signaling is a novel redox signaling pathway that links mechanical stress to changes in [Ca2+]i. This pathway is activated rapidly and locally within a muscle cell under physiological conditions, but can also contribute to Ca2+-dependent arrhythmia in heart and to the dystrophic phenotype in heart and skeletal muscle 1, 2. Upon physiologic cellular stretch, microtubules serve as mechanotransducers to activate NADPH oxidase 2 (NOX2) in the transverse tubules and sarcolemmal membranes to produce reactive oxygen species (ROS). In heart, the ROS acts locally to activate ryanodine receptor Ca2+ release channels in the junctional sarcoplasmic reticulum, increasing the Ca2+ spark rate and "tuning" excitation-contraction coupling. In skeletal muscle, where Ca2+ sparks are not normally observed, the X-ROS signaling process is muted. However in muscular dystrophies, such as Duchenne Muscular Dystrophy and dysferlinopathy, X-ROS signaling operates at a high level and contributes to myopathy. Importantly, in skeletal muscle Ca2+ permeable stretch-activated channels are activated by X-ROS and contribute to the cellular pathology. In brief, X-ROS provides an exciting new mechanism for the mechanical control of redox and Ca2+ signaling in cardiac and skeletal muscle.
1. Khairallah RJ, Shi G, Sbrana F, Prosser BL, Borroto C, Mazaitis MJ, Hoffman EP, Mahurkar A, Sachs F, Sun Y, Chen YW, Raiteri R, Lederer WJ, Dorsey SG, Ward CW. Microtubules underlie dysfunction in duchenne muscular dystrophy. Sci Signal. 2012;5:ra56
2. Prosser BL, Ward CW, Lederer WJ. X-ros signaling: Rapid mechano-chemo transduction in heart. Science. 2011;333:1440-1445