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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 the heart and to the dystrophic phenotype in the heart and skeletal muscle. Upon physiologic cellular stretch, microtubules serve as mechanotransducers to activate NADPH oxidase 2 in the transverse tubules and sarcolemmal membranes to produce reactive oxygen species (ROS). In the 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 the skeletal muscle, where Ca²⁺ sparks are not normally observed, the X-ROS signaling process is muted. However in muscular dystrophies, such as Duchenne Muscular …