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


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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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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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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The authors declare no competing financial interests.

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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).

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