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...
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| Veröffentlicht in: | Nature cell biology 2009-06, Vol.11 (6), p.769-776 |
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| creator | Shen, Jinhua Yu, Wen-Mei Brotto, Marco Scherman, Joseph A. Guo, Caiying Stoddard, Christopher Nosek, Thomas M. Valdivia, Héctor H. Qu, Cheng-Kui |
| description | 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. |
| doi_str_mv | 10.1038/ncb1884 |
| format | Article |
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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.</description><identifier>ISSN: 1465-7392</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/ncb1884</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Biomedical and Life Sciences ; Cancer Research ; Cell Biology ; Developmental Biology ; Fatigue ; Fitness equipment ; Genomes ; Heart ; Homeostasis ; letter ; Life Sciences ; Medical research ; Muscles ; Mutation ; Phosphatase ; Physiology ; Proteins ; Stem Cells</subject><ispartof>Nature cell biology, 2009-06, Vol.11 (6), p.769-776</ispartof><rights>Springer Nature Limited 2009</rights><rights>Copyright Nature Publishing Group Jun 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c314t-bb7271574788178680dba2262ef5781890fc6b708607de884c2e4945e1d456613</citedby><cites>FETCH-LOGICAL-c314t-bb7271574788178680dba2262ef5781890fc6b708607de884c2e4945e1d456613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids></links><search><creatorcontrib>Shen, Jinhua</creatorcontrib><creatorcontrib>Yu, Wen-Mei</creatorcontrib><creatorcontrib>Brotto, Marco</creatorcontrib><creatorcontrib>Scherman, Joseph A.</creatorcontrib><creatorcontrib>Guo, Caiying</creatorcontrib><creatorcontrib>Stoddard, Christopher</creatorcontrib><creatorcontrib>Nosek, Thomas M.</creatorcontrib><creatorcontrib>Valdivia, Héctor H.</creatorcontrib><creatorcontrib>Qu, Cheng-Kui</creatorcontrib><title>Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis</title><title>Nature cell biology</title><addtitle>Nat Cell Biol</addtitle><description>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.</description><subject>Biomedical and Life Sciences</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Developmental Biology</subject><subject>Fatigue</subject><subject>Fitness equipment</subject><subject>Genomes</subject><subject>Heart</subject><subject>Homeostasis</subject><subject>letter</subject><subject>Life Sciences</subject><subject>Medical research</subject><subject>Muscles</subject><subject>Mutation</subject><subject>Phosphatase</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Stem Cells</subject><issn>1465-7392</issn><issn>1476-4679</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkF9LwzAUxYMoOKf4FYIvClKXm6ZJ-ijz32BDkfkoJU1vt46tqUn7sG9vRweC9-Weh989l3MIuQb2ACzWk9rmoLU4ISMQSkZCqvT0oGUSqTjl5-QihA1jIARTI_L9hGVlK6ztnrqSLmYfk8Vy8QmCNmsXmrVpTUBa1UVnMVBDd12wW6RFFZwv0NN8f9C-a9qqXtGp4fd07XboQn9XhUtyVpptwKvjHpOvl-fl9C2av7_Opo_zyMYg2ijPFVeQKKG0BqWlZkVuOJccy0Rp0CkrrcwV05KpAvtwlqNIRYJQiERKiMfkZvBtvPvpMLTZxnW-7l9mvB8FAngP3Q6Q9S4Ej2XW-Gpn_D4Dlh2qy47V9eTdQIaeqFfo_-z-o7_9smxu</recordid><startdate>20090601</startdate><enddate>20090601</enddate><creator>Shen, Jinhua</creator><creator>Yu, Wen-Mei</creator><creator>Brotto, Marco</creator><creator>Scherman, Joseph A.</creator><creator>Guo, Caiying</creator><creator>Stoddard, Christopher</creator><creator>Nosek, Thomas M.</creator><creator>Valdivia, Héctor H.</creator><creator>Qu, Cheng-Kui</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope></search><sort><creationdate>20090601</creationdate><title>Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis</title><author>Shen, Jinhua ; Yu, Wen-Mei ; Brotto, Marco ; Scherman, Joseph A. ; Guo, Caiying ; Stoddard, Christopher ; Nosek, Thomas M. ; Valdivia, Héctor H. ; Qu, Cheng-Kui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c314t-bb7271574788178680dba2262ef5781890fc6b708607de884c2e4945e1d456613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Biomedical and Life Sciences</topic><topic>Cancer Research</topic><topic>Cell Biology</topic><topic>Developmental Biology</topic><topic>Fatigue</topic><topic>Fitness equipment</topic><topic>Genomes</topic><topic>Heart</topic><topic>Homeostasis</topic><topic>letter</topic><topic>Life Sciences</topic><topic>Medical research</topic><topic>Muscles</topic><topic>Mutation</topic><topic>Phosphatase</topic><topic>Physiology</topic><topic>Proteins</topic><topic>Stem Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shen, Jinhua</creatorcontrib><creatorcontrib>Yu, Wen-Mei</creatorcontrib><creatorcontrib>Brotto, Marco</creatorcontrib><creatorcontrib>Scherman, Joseph A.</creatorcontrib><creatorcontrib>Guo, Caiying</creatorcontrib><creatorcontrib>Stoddard, Christopher</creatorcontrib><creatorcontrib>Nosek, Thomas M.</creatorcontrib><creatorcontrib>Valdivia, Héctor H.</creatorcontrib><creatorcontrib>Qu, Cheng-Kui</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><jtitle>Nature cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shen, Jinhua</au><au>Yu, Wen-Mei</au><au>Brotto, Marco</au><au>Scherman, Joseph A.</au><au>Guo, Caiying</au><au>Stoddard, Christopher</au><au>Nosek, Thomas M.</au><au>Valdivia, Héctor H.</au><au>Qu, Cheng-Kui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis</atitle><jtitle>Nature cell biology</jtitle><stitle>Nat Cell Biol</stitle><date>2009-06-01</date><risdate>2009</risdate><volume>11</volume><issue>6</issue><spage>769</spage><epage>776</epage><pages>769-776</pages><issn>1465-7392</issn><eissn>1476-4679</eissn><abstract>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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><doi>10.1038/ncb1884</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| subjects | Biomedical and Life Sciences Cancer Research Cell Biology Developmental Biology Fatigue Fitness equipment Genomes Heart Homeostasis letter Life Sciences Medical research Muscles Mutation Phosphatase Physiology Proteins Stem Cells |
| title | Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca2+ homeostasis |
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