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

• Published in: Nature cell biology Vol. 11; no. 6; p. 769
• Main Authors: Shen, Jinhua, Yu, Wen-Mei, Brotto, Marco, Scherman, Joseph A, Guo, Caiying, Stoddard, Christopher, Nosek, Thomas M, Valdivia, Héctor H, Qu, Cheng-Kui
• Format: Journal Article
• Language: English
• Published: England 01.06.2009
• Subjects: Amino Acid Sequence; Animals; Calcium - metabolism; Calcium Signaling - physiology; Electrophysiology; Female; Heart - anatomy & histology; Homeostasis; Humans; Mice; Mice, Knockout; Molecular Sequence Data; Muscle, Skeletal - cytology; Muscle, Skeletal - physiology; Muscular Diseases - enzymology; Myocardial Contraction - physiology; Myocardium - metabolism; Phosphatidylinositol Phosphates - chemistry; Phosphatidylinositol Phosphates - metabolism; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - genetics; Rabbits; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Sequence Alignment; Sequence Homology, Amino Acid; Tissue Distribution
• ISSN: 1476-4679
• DOI: 10.1038/ncb1884

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.