Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting [Ca.sup.2+] homeostasis

The intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) in skeletal muscles must be rapidly regulated during the excitation-contraction-relaxation process (1). However, the signalling components involved in such rapid [Ca.sup.2+] movement are not fully understood. Here we report that mic...

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Bibliographic Details
Published inNature cell biology Vol. 11; no. 6; pp. 769 - 790
Main Authors Shen, Jinhua, Yu, Wen-Mei, Brotto, Marco, Scherman, Joseph A, Guo, Caiying, Stoddard, Christopher, Nosek, Thomas M, Valdivia, Hector H, Qu, Cheng-Kui
Format Journal Article
LanguageEnglish
Published Nature Publishing Group 01.06.2009
Subjects
Calcium ions
Muscle diseases
Phosphatases
Physiological aspects
Risk factors
United States
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Summary:The intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) in skeletal muscles must be rapidly regulated during the excitation-contraction-relaxation process (1). However, the signalling components involved in such rapid [Ca.sup.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/ MTMR[14.sup.-/-] 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.sup.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.sub.2] and PtdIns (3,4)[P.sub.2]. Furthermore, we found that PtdIns(3,5)[P.sub.2] and PtdIns(3,4)[P.sub.2] bound to, and directly activated, the [Ca.sup.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.sup.2+] homeostasis and muscle performance.
ISSN:1465-7392
1476-4679