Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy
Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertoo...
Gespeichert in:
| Veröffentlicht in: | Human molecular genetics 2012-01, Vol.21 (1), p.185-195 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 195 |
|---|---|
| container_issue | 1 |
| container_start_page | 185 |
| container_title | Human molecular genetics |
| container_volume | 21 |
| creator | Ling, Karen K. Y. Gibbs, Rebecca M. Feng, Zhihua Ko, Chien-Ping |
| description | Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation ( |
| doi_str_mv | 10.1093/hmg/ddr453 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3235013</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/hmg/ddr453</oup_id><sourcerecordid>920804068</sourcerecordid><originalsourceid>FETCH-LOGICAL-c576t-c3cf47927abef735d2763d5d6b232f5cb0419b4cd58416b4d7598dbcd36961703</originalsourceid><addsrcrecordid>eNqF0U2L1DAYB_AgijuuXvwAkosIQt2keWsuwrL4Bgse1HNIk6c70TSpSTsw394OM87qRS_JIT_-yZM_Qs8peUOJZlfb8e7K-8IFe4A2lEvStKRjD9GGaMkbqYm8QE9q_U4IlZypx-iipVp2gvIN-vEFdlAAJ1hKHpfqlmgL9pCg7OwccsJ5wC6GFJyNcY8LRNjZNOODjVBxSNjiMS8V1tVDPPg6hWQjPsfZueRpu3-KHg02Vnh22i_Rt_fvvt58bG4_f_h0c33bOKHk3DjmBq50q2wPg2LCt0oyL7zsW9YOwvWEU91z50XHqey5V0J3vneeSS2pIuwSvT3mTks_gneQ5mKjmUoYbdmbbIP5-ySFrbnLO8NaJghla8CrU0DJPxeosxlDdRCjTbBOavT6v4QT2f1fUqpZq7qDfH2UruRaCwzn91BiDjWatUZzrHHFL_6c4Ex_97aClydg61rMUGxyod47IXinCbl3eZn-deEvAP-13w</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>911932788</pqid></control><display><type>article</type><title>Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Ling, Karen K. Y. ; Gibbs, Rebecca M. ; Feng, Zhihua ; Ko, Chien-Ping</creator><creatorcontrib>Ling, Karen K. Y. ; Gibbs, Rebecca M. ; Feng, Zhihua ; Ko, Chien-Ping</creatorcontrib><description>Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddr453</identifier><identifier>PMID: 21968514</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Animal models ; Animals ; Biological and medical sciences ; Cell survival ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Denervation ; Disease Models, Animal ; Fundamental and applied biological sciences. Psychology ; Genetics of eukaryotes. Biological and molecular evolution ; Innervation ; Male ; Medical sciences ; Mice ; Mice, Knockout ; Mice, Transgenic ; Molecular and cellular biology ; Motor neurons ; Muscle Denervation ; Muscle, Skeletal - innervation ; Muscle, Skeletal - pathology ; Muscle, Skeletal - surgery ; Muscles ; Muscular Atrophy, Spinal - metabolism ; Muscular Atrophy, Spinal - pathology ; Muscular Atrophy, Spinal - surgery ; Nerve Degeneration ; Neurofilaments ; Neurology ; Neuromuscular Junction - metabolism ; Neuromuscular Junction - surgery ; Neuromuscular junctions ; SMN protein ; spinal muscular atrophy ; Synapses ; Synapses - metabolism ; Synapses - pathology ; Trichostatin A</subject><ispartof>Human molecular genetics, 2012-01, Vol.21 (1), p.185-195</ispartof><rights>The Author 2011. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2011</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c576t-c3cf47927abef735d2763d5d6b232f5cb0419b4cd58416b4d7598dbcd36961703</citedby><cites>FETCH-LOGICAL-c576t-c3cf47927abef735d2763d5d6b232f5cb0419b4cd58416b4d7598dbcd36961703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25548900$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21968514$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ling, Karen K. Y.</creatorcontrib><creatorcontrib>Gibbs, Rebecca M.</creatorcontrib><creatorcontrib>Feng, Zhihua</creatorcontrib><creatorcontrib>Ko, Chien-Ping</creatorcontrib><title>Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.</description><subject>Animal models</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell survival</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Denervation</subject><subject>Disease Models, Animal</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Innervation</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Molecular and cellular biology</subject><subject>Motor neurons</subject><subject>Muscle Denervation</subject><subject>Muscle, Skeletal - innervation</subject><subject>Muscle, Skeletal - pathology</subject><subject>Muscle, Skeletal - surgery</subject><subject>Muscles</subject><subject>Muscular Atrophy, Spinal - metabolism</subject><subject>Muscular Atrophy, Spinal - pathology</subject><subject>Muscular Atrophy, Spinal - surgery</subject><subject>Nerve Degeneration</subject><subject>Neurofilaments</subject><subject>Neurology</subject><subject>Neuromuscular Junction - metabolism</subject><subject>Neuromuscular Junction - surgery</subject><subject>Neuromuscular junctions</subject><subject>SMN protein</subject><subject>spinal muscular atrophy</subject><subject>Synapses</subject><subject>Synapses - metabolism</subject><subject>Synapses - pathology</subject><subject>Trichostatin A</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0U2L1DAYB_AgijuuXvwAkosIQt2keWsuwrL4Bgse1HNIk6c70TSpSTsw394OM87qRS_JIT_-yZM_Qs8peUOJZlfb8e7K-8IFe4A2lEvStKRjD9GGaMkbqYm8QE9q_U4IlZypx-iipVp2gvIN-vEFdlAAJ1hKHpfqlmgL9pCg7OwccsJ5wC6GFJyNcY8LRNjZNOODjVBxSNjiMS8V1tVDPPg6hWQjPsfZueRpu3-KHg02Vnh22i_Rt_fvvt58bG4_f_h0c33bOKHk3DjmBq50q2wPg2LCt0oyL7zsW9YOwvWEU91z50XHqey5V0J3vneeSS2pIuwSvT3mTks_gneQ5mKjmUoYbdmbbIP5-ySFrbnLO8NaJghla8CrU0DJPxeosxlDdRCjTbBOavT6v4QT2f1fUqpZq7qDfH2UruRaCwzn91BiDjWatUZzrHHFL_6c4Ex_97aClydg61rMUGxyod47IXinCbl3eZn-deEvAP-13w</recordid><startdate>20120101</startdate><enddate>20120101</enddate><creator>Ling, Karen K. Y.</creator><creator>Gibbs, Rebecca M.</creator><creator>Feng, Zhihua</creator><creator>Ko, Chien-Ping</creator><general>Oxford University Press</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20120101</creationdate><title>Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy</title><author>Ling, Karen K. Y. ; Gibbs, Rebecca M. ; Feng, Zhihua ; Ko, Chien-Ping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c576t-c3cf47927abef735d2763d5d6b232f5cb0419b4cd58416b4d7598dbcd36961703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell survival</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Denervation</topic><topic>Disease Models, Animal</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>Innervation</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Molecular and cellular biology</topic><topic>Motor neurons</topic><topic>Muscle Denervation</topic><topic>Muscle, Skeletal - innervation</topic><topic>Muscle, Skeletal - pathology</topic><topic>Muscle, Skeletal - surgery</topic><topic>Muscles</topic><topic>Muscular Atrophy, Spinal - metabolism</topic><topic>Muscular Atrophy, Spinal - pathology</topic><topic>Muscular Atrophy, Spinal - surgery</topic><topic>Nerve Degeneration</topic><topic>Neurofilaments</topic><topic>Neurology</topic><topic>Neuromuscular Junction - metabolism</topic><topic>Neuromuscular Junction - surgery</topic><topic>Neuromuscular junctions</topic><topic>SMN protein</topic><topic>spinal muscular atrophy</topic><topic>Synapses</topic><topic>Synapses - metabolism</topic><topic>Synapses - pathology</topic><topic>Trichostatin A</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ling, Karen K. Y.</creatorcontrib><creatorcontrib>Gibbs, Rebecca M.</creatorcontrib><creatorcontrib>Feng, Zhihua</creatorcontrib><creatorcontrib>Ko, Chien-Ping</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ling, Karen K. Y.</au><au>Gibbs, Rebecca M.</au><au>Feng, Zhihua</au><au>Ko, Chien-Ping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2012-01-01</date><risdate>2012</risdate><volume>21</volume><issue>1</issue><spage>185</spage><epage>195</epage><pages>185-195</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>21968514</pmid><doi>10.1093/hmg/ddr453</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0964-6906 |
| ispartof | Human molecular genetics, 2012-01, Vol.21 (1), p.185-195 |
| issn | 0964-6906 1460-2083 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3235013 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animal models Animals Biological and medical sciences Cell survival Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Denervation Disease Models, Animal Fundamental and applied biological sciences. Psychology Genetics of eukaryotes. Biological and molecular evolution Innervation Male Medical sciences Mice Mice, Knockout Mice, Transgenic Molecular and cellular biology Motor neurons Muscle Denervation Muscle, Skeletal - innervation Muscle, Skeletal - pathology Muscle, Skeletal - surgery Muscles Muscular Atrophy, Spinal - metabolism Muscular Atrophy, Spinal - pathology Muscular Atrophy, Spinal - surgery Nerve Degeneration Neurofilaments Neurology Neuromuscular Junction - metabolism Neuromuscular Junction - surgery Neuromuscular junctions SMN protein spinal muscular atrophy Synapses Synapses - metabolism Synapses - pathology Trichostatin A |
| title | Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T17%3A13%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Severe%20neuromuscular%20denervation%20of%20clinically%20relevant%20muscles%20in%20a%20mouse%20model%20of%20spinal%20muscular%20atrophy&rft.jtitle=Human%20molecular%20genetics&rft.au=Ling,%20Karen%20K.%20Y.&rft.date=2012-01-01&rft.volume=21&rft.issue=1&rft.spage=185&rft.epage=195&rft.pages=185-195&rft.issn=0964-6906&rft.eissn=1460-2083&rft_id=info:doi/10.1093/hmg/ddr453&rft_dat=%3Cproquest_pubme%3E920804068%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=911932788&rft_id=info:pmid/21968514&rft_oup_id=10.1093/hmg/ddr453&rfr_iscdi=true |