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- Title
Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca<sup>2+</sup> homeostasis.
- Authors
Jinhua Shen; Wen-Mei Yu; Brotto, Marco; Scherman, Joseph A.; Guo, Caiying; Stoddard, Christopher; Nosek, Thomas M.; Valdivia, Héctor H.; Cheng-Kui Qu
- Abstract
The intracellular Ca2+ concentration ([Ca2+]i) in skeletal muscles must be rapidly regulated during the excitation-contraction-relaxation process. 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.
- Subjects
CALCIUM ions; MUSCLE cells; MUSCLES; HOMEOSTASIS; PROTEINS; PHOSPHATASES
- Publication
Nature Cell Biology, 2009, Vol 11, Issue 6, p769
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb1884