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We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where NOX2 is located and sensitizes nearby ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). This triggers a burst of Ca²⁺ sparks, the elementary Ca²⁺ release events in heart. Although this stretch-dependent “tuning” of RyRs increases Ca²⁺ signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca²⁺ sparks to trigger arrhythmogenic Ca²⁺ waves. In the mouse model of Duchenne muscular dystrophy, hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca²⁺ release from the SR. X-ROS signaling thus provides a mechanistic …