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Most excitable cells maintain tight control of intracellular Ca²⁺ through coordinated interaction between plasma membrane and endoplasmic or sarcoplasmic reticulum. Quiescent sarcoplasmic reticulum Ca²⁺ release machinery is essential for the survival and normal function of skeletal muscle^,,. Here we show that subtle membrane deformations induce Ca²⁺ sparks in intact mammalian skeletal muscle. Spontaneous Ca²⁺ sparks can be reversibly induced by osmotic shock, and participate in a normal physiological response to exercise. In dystrophic muscle with fragile membrane integrity, stress-induced Ca²⁺ sparks are essentially irreversible. Moreover, moderate exercise in mdx muscle alters the Ca²⁺ spark response. Thus, membrane-deformation-induced Ca²⁺ sparks have an important role in physiological and pathophysiological regulation of Ca²⁺ signalling, and uncontrolled Ca²⁺ spark activity in …