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Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca(2+) homeostasis.


The intracellular Ca(2+) concentration ([Ca(2+)](i)) in skeletal muscles must be rapidly regulated during the excitation-contraction-relaxation process. However, the signalling components involved in such rapid Ca(2+) 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 Ca(2+) 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)P(2) and PtdIns (3,4)P(2). Furthermore, we found that PtdIns(3,5)P(2) and PtdIns(3,4)P(2) bound to, and directly activated, the Ca(2+) 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 Ca(2+) homeostasis and muscle performance.

Pubmed ID: 19465920


  • Shen J
  • Yu WM
  • Brotto M
  • Scherman JA
  • Guo C
  • Stoddard C
  • Nosek TM
  • Valdivia HH
  • Qu CK


Nature cell biology

Publication Data

June 8, 2009

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL068212
  • Agency: NHLBI NIH HHS, Id: HL082670
  • Agency: NHLBI NIH HHS, Id: HL55438
  • Agency: NHLBI NIH HHS, Id: R01 HL055438
  • Agency: NHLBI NIH HHS, Id: R01 HL068212
  • Agency: NHLBI NIH HHS, Id: R01 HL068212-06
  • Agency: NHLBI NIH HHS, Id: R21 HL082670
  • Agency: NHLBI NIH HHS, Id: R21 HL082670-02

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Calcium
  • Calcium Signaling
  • Electrophysiology
  • Female
  • Heart
  • Homeostasis
  • Humans
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Muscle, Skeletal
  • Muscular Diseases
  • Myocardial Contraction
  • Myocardium
  • Phosphatidylinositol Phosphates
  • Phosphoric Monoester Hydrolases
  • Rabbits
  • Ryanodine Receptor Calcium Release Channel
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Tissue Distribution