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Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis

Nature Cell Biology volume 11, pages 769–776 (2009)Cite this article

Abstract

The intracellular Ca2+ concentration ([Ca2+]i) in skeletal muscles must be rapidly regulated during the excitation-contraction-relaxation process1. However, the signalling components involved in such rapid Ca2+ movement are not fully understood. Here we report that mice deficient in the newly identified PtdInsP (phosphatidylinositol phosphate) phosphatase MIP/MTMR14 (muscle-specific inositol phosphatase) show muscle weakness and fatigue. Muscles isolated from MIP/MTMR14−/− mice produced less contractile force, had markedly prolonged relaxation and showed exacerbated fatigue relative to normal muscles. Further analyses revealed that MIP/MTMR14 deficiency resulted in spontaneous Ca2+ leakage from the internal store — the sarcoplasmic reticulum. This was attributed to decreased metabolism (dephosphorylation) and the subsequent accumulation of MIP/MTMR14 substrates, especially PtdIns(3,5)P2 and PtdIns (3,4)P2. Furthermore, we found that PtdIns(3,5)P2 and PtdIns(3,4)P2 bound to, and directly activated, the Ca2+ release channel (ryanodine receptor 1, RyR1) of the sarcoplasmic reticulum. These studies provide the first evidence that finely controlled PtdInsP levels in muscle cells are essential for maintaining Ca2+ homeostasis and muscle performance.

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Figure 1: Characterization of human MIP.
Figure 2: Decreased force production, prolonged relaxation and exacerbated fatigue in MIP−/− muscles.
Figure 3: Compromised store-operated Ca2+ signalling in MIP−/− muscle cells.
Figure 4: Perfusion of PtdIns(3,5)P2, PtdIns(3,4)P2 and PtdIns(3)P (to a lesser extent) into wild-type myotubes results in aberrant Ca2+ signalling.
Figure 5: Activation of the skeletal muscle RyR1 Ca2+ channel by PtdInsPs.

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Acknowledgements

We are grateful to D. Chess, M. Chandler, T. Stefan, J. Jacobberger, L. Brotto, N. Wiesleder and J. Ma for technical assistance and helpful discussions. Motor function tests were performed by the Case Western Reserve University Rodent Behavior Core. This work was supported by NIH grants (HL068212 and HL082670) to C.K.Q. and (HL55438) H.H.V., an American Heart Association grant (0535555N) to M.B. and a pilot grant from the Case Center for Transdisciplinary Research on Energetics and Cancer to T.M.N., C.K.Q. and M.B.

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Author notes

  1. Jinhua Shen, Wen-Mei Yu and Marco Brotto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, 44106, OH, USA

    Jinhua Shen, Wen-Mei Yu & Cheng-Kui Qu

  2. Schools of Nursing and Medicine, University of Missouri, Kansas City, 64108, MO, USA

    Marco Brotto

  3. Department of Physiology, University of Wisconsin Medical School, Madison, 53706, WI, USA

    Joseph A. Scherman & Héctor H. Valdivia

  4. Gene Targeting and Transgenic Facility, University of Connecticut Health Center, Farmington, 06030, CT, USA

    Caiying Guo & Christopher Stoddard

  5. Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, 44106, OH, USA

    Thomas M. Nosek

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Contributions

J.S., W.M.Y., M.B., J.A.S. and C.S. conducted the research and summarized the data, and C.K.Q., M.B., H.H.V., T.M.N. and C.G. designed the experiments and wrote the manuscript.

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Correspondence to Cheng-Kui Qu.

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Shen, J., Yu, WM., Brotto, M. et al. Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis. Nat Cell Biol 11, 769–776 (2009). https://doi.org/10.1038/ncb1884

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