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Uncontrolled calcium sparks act as a dystrophic signal for mammalian skeletal muscle

Abstract

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 muscle1,2,3. 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 connection with chronic activation of store-operated Ca2+ entry may function as a dystrophic signal in mammalian skeletal muscle.

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Figure 1: Osmotic-shock-induced Ca2+ spark activity in intact mouse skeletal muscle.
Figure 2: Irreversible Ca2+ spark activity in mdx skeletal muscle in response to membrane deformation.
Figure 3: Differential properties of Ca2+ signalling in wild-type and mdx muscle.
Figure 4: Exercise-induced Ca2+ sparks in mdx and wild-type skeletal muscle.
Figure 5: Schematic diagram for the control of Ca2+ sparks in mammalian skeletal muscle.

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Acknowledgements

This work was supported by NIH grants awarded to J.M. (RO1-AG15556, RO1-CA95739 and RO1-HL69000), and an AHA postdoctoral fellowship to N.W. We thank J. Lederer and E. Rios for critical discussion and suggestions to this work, and C. Franzini-Armstrong, Y. Shi and J. Parness for helpful comments.

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Correspondence to Jianjie Ma.

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Wang, X., Weisleder, N., Collet, C. et al. Uncontrolled calcium sparks act as a dystrophic signal for mammalian skeletal muscle. Nat Cell Biol 7, 525–530 (2005). https://doi.org/10.1038/ncb1254

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