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

Mutations in the MIP phosphatase MTMR14 are associated with human autosomal centronuclear myopathy. Mice that lack MIP have impaired muscle performance and enhanced fatigue due to the accumulation of MIP substrates PtdIns(3,5)P2 and PtdIns(3,4)P2, which cause alterations in intracellular Ca2+ levels. The intracellular Ca 2+ concentration ([Ca 2+ ] i ) in skeletal muscles must be rapidly regulated during the excitation-contraction-relaxation process 1 . 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.