| First Author | Shen J | Year | 2009 |
| Journal | Nat Cell Biol | Volume | 11 |
| Issue | 6 | Pages | 769-76 |
| PubMed ID | 19465920 | Mgi Jnum | J:155068 |
| Mgi Id | MGI:4412221 | Doi | 10.1038/ncb1884 |
| Citation | Shen J, et al. (2009) Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca(2+) homeostasis. Nat Cell Biol 11(6):769-76 |
| abstractText | 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. |
