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STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle

Nature Cell Biology volume 10, pages 688–697 (2008)Cite this article

Abstract

It is now well established that stromal interaction molecule 1 (STIM1) is the calcium sensor of endoplasmic reticulum stores required to activate store-operated calcium entry (SOC) channels at the surface of non-excitable cells. However, little is known about STIM1 in excitable cells, such as striated muscle, where the complement of calcium regulatory molecules is rather disparate from that of non-excitable cells. Here, we show that STIM1 is expressed in both myotubes and adult skeletal muscle. Myotubes lacking functional STIM1 fail to show SOC and fatigue rapidly. Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy. In addition, STIM1 haploinsufficiency confers a contractile defect only under conditions where rapid refilling of stores would be needed. These findings provide insight into the role of STIM1 in skeletal muscle and suggest that STIM1 has a universal role as an ER/SR calcium sensor in both excitable and non-excitable cells.

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Figure 1: Muscle differentiation is associated with increased expression of STIM1 and redistribution of STIM1.
Figure 2: Gene trap strategy for STIM1.
Figure 3: Store depletion fails to activate SOC current in primary myotubes lacking functional STIM1.
Figure 4: STIM1 Localization.
Figure 5: Mice without functional STIM1 show a neonatal skeletal myopathy.
Figure 6: Muscle gene expression and functional analysis of STIM1-mutant mice.
Figure 7: STIM1-mediated store refilling is required for fatigue resistance in skeletal myotubes.

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Acknowledgements

Special thanks to Mary Hutson for her guidance on whole-mount in situ hybridization and imaging techniques and to Margaret Kirby's lab for providing imaging equipment. We thank Gerhard Meissner and Qui-An Sun for their help with microsomal preparations. This research was carried out at the Sarah W. Stedman Nutrition and Metabolism Center at Duke University and supported by the following grants: an HHMI Physician-Scientist Early Career Award and NIH award (K08-HL077520) to J.A.S., NIH award (K08-HL-071841-04), Mandel Foundation award and MDA research award to P.B.R., and an HHMI Training Fellowship for Medical Students to S.W.

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  1. Jonathan Stiber, April Hawkins and Zhu-Shan Zhang: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Duke University School of Medicine, Durham, NC

    Jonathan Stiber, April Hawkins, Zhu-Shan Zhang, Sunny Wang, Jarrett Burch, Victoria Graham, Cary C. Ward, Malini Seth, Elizabeth Finch, R. Sanders Williams, Jerry P. Eu & Paul Rosenberg

  2. Department of Pathology, University of North Carolina, Chapel Hill, NC, USA

    Nadia Malouf

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Contributions

J.S. carried out the confocal imaging and contributed to the calcium imaging experiments; A.F. and S.W. generated the Stim1 gene trap mice and isolated primary and cultured myotubes; Z.S.Z. designed and executed all patch-clamp experiments; V.G. prepared all samples for electron microscopy and confocal imaging; J.B. and E.F. performed all calcium imaging experiments and analysed the data; M.S. generated silencing adenoviruses; N.M. interpreted the electron microscopy studies; J.E. performed force-frequency experiments; R.S.W. contributed to the writing of the manuscript; P.R. planned the experiments, analysed the data and wrote the manuscript.

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Correspondence to Paul Rosenberg.

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Stiber, J., Hawkins, A., Zhang, ZS. et al. STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nat Cell Biol 10, 688–697 (2008). https://doi.org/10.1038/ncb1731

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