Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy
Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanism...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ottenheijm, Coen Adri Charles - 1976- [verfasserIn] Buck, Danielle [verfasserIn] de Winter, Josine M. [verfasserIn] Ferrara, Claudia [verfasserIn] Piroddi, Nicoletta [verfasserIn] Tesi, Chiara [verfasserIn] Jasper, Jeffrey R. [verfasserIn] Malik, Fady I. [verfasserIn] Meng, Hui [verfasserIn] Stienen, Ger J. M. [verfasserIn] Beggs, Alan H. [verfasserIn] Labeit, Siegfried - 1960- [verfasserIn] Poggesi, Corrado [verfasserIn] Lawlor, Michael W. [verfasserIn] Granzier, Henk [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
28 May 2013 |
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| Anmerkung: |
Gesehen am 31.03.2022 |
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| Umfang: |
14 |
| Weitere Ausgabe: |
Erscheint auch als Druck-Ausgabe Ottenheijm, Coen Adri Charles, 1976 -: Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy - 2013 |
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| Übergeordnetes Werk: |
Enthalten in: Brain - Oxford : Oxford Univ. Press, 1878, 136(2013), 6, Seite 1718-1731 |
| Übergeordnetes Werk: |
volume:136 ; year:2013 ; number:6 ; pages:1718-1731 ; extent:14 |
| Links: |
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| DOI / URN: |
10.1093/brain/awt113 |
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| Katalog-ID: |
1797149970 |
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| 245 | 1 | 0 | |a Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy |c Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit, Corrado Poggesi, Michael W. Lawlor and Henk Granzier |
| 264 | 1 | |c 28 May 2013 | |
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| 520 | |a Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. | ||
| 700 | 1 | |a Buck, Danielle |e verfasserin |4 aut | |
| 700 | 1 | |a de Winter, Josine M. |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrara, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Piroddi, Nicoletta |e verfasserin |4 aut | |
| 700 | 1 | |a Tesi, Chiara |e verfasserin |4 aut | |
| 700 | 1 | |a Jasper, Jeffrey R. |e verfasserin |4 aut | |
| 700 | 1 | |a Malik, Fady I. |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Stienen, Ger J. M. |e verfasserin |4 aut | |
| 700 | 1 | |a Beggs, Alan H. |e verfasserin |4 aut | |
| 700 | 1 | |a Labeit, Siegfried |d 1960- |e verfasserin |0 (DE-588)1033566837 |0 (DE-627)741562375 |0 (DE-576)381187314 |4 aut | |
| 700 | 1 | |a Poggesi, Corrado |e verfasserin |4 aut | |
| 700 | 1 | |a Lawlor, Michael W. |e verfasserin |4 aut | |
| 700 | 1 | |a Granzier, Henk |e verfasserin |4 aut | |
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| 776 | 0 | 8 | |i Erscheint auch als |n Druck-Ausgabe |a Ottenheijm, Coen Adri Charles, 1976 - |t Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy |d 2013 |w (DE-627)1632717085 |w (DE-576)391846418 |
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10.1093/brain/awt113 doi (DE-627)1797149970 (DE-599)KXP1797149970 (OCoLC)1341458280 DE-627 ger DE-627 rda eng Ottenheijm, Coen Adri Charles 1976- verfasserin (DE-588)1012497054 (DE-627)661828646 (DE-576)345492889 aut Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit, Corrado Poggesi, Michael W. Lawlor and Henk Granzier 28 May 2013 14 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.03.2022 Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Buck, Danielle verfasserin aut de Winter, Josine M. verfasserin aut Ferrara, Claudia verfasserin aut Piroddi, Nicoletta verfasserin aut Tesi, Chiara verfasserin aut Jasper, Jeffrey R. verfasserin aut Malik, Fady I. verfasserin aut Meng, Hui verfasserin aut Stienen, Ger J. M. verfasserin aut Beggs, Alan H. verfasserin aut Labeit, Siegfried 1960- verfasserin (DE-588)1033566837 (DE-627)741562375 (DE-576)381187314 aut Poggesi, Corrado verfasserin aut Lawlor, Michael W. verfasserin aut Granzier, Henk verfasserin aut Enthalten in Brain Oxford : Oxford Univ. Press, 1878 136(2013), 6, Seite 1718-1731 Online-Ressource (DE-627)269242562 (DE-600)1474117-9 (DE-576)079718728 1460-2156 nnns volume:136 year:2013 number:6 pages:1718-1731 extent:14 Erscheint auch als Druck-Ausgabe Ottenheijm, Coen Adri Charles, 1976 - Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy 2013 (DE-627)1632717085 (DE-576)391846418 https://doi.org/10.1093/brain/awt113 Verlag Resolving-System lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_121 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_374 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2043 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2098 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2145 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2158 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2810 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4346 GBV_ILN_4367 GBV_ILN_4392 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_4753 AR 136 2013 6 1718-1731 14 2013 01 DE-16-250 4108094824 00 --%%-- --%%-- --%%-- --%%-- l01 31-03-22 2013 01 DE-16-250 00 s hd2013 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_15 2013 01 DE-16-250 03 s s_14 2013 01 DE-16-250 04 p (DE-627)1451187556 Labeit, Siegfried 2013 01 DE-16-250 04 k (DE-627)1416467890 Klinik für Anästhesiologie und Operative Intensivmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_12 |
| spelling |
10.1093/brain/awt113 doi (DE-627)1797149970 (DE-599)KXP1797149970 (OCoLC)1341458280 DE-627 ger DE-627 rda eng Ottenheijm, Coen Adri Charles 1976- verfasserin (DE-588)1012497054 (DE-627)661828646 (DE-576)345492889 aut Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit, Corrado Poggesi, Michael W. Lawlor and Henk Granzier 28 May 2013 14 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.03.2022 Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Buck, Danielle verfasserin aut de Winter, Josine M. verfasserin aut Ferrara, Claudia verfasserin aut Piroddi, Nicoletta verfasserin aut Tesi, Chiara verfasserin aut Jasper, Jeffrey R. verfasserin aut Malik, Fady I. verfasserin aut Meng, Hui verfasserin aut Stienen, Ger J. M. verfasserin aut Beggs, Alan H. verfasserin aut Labeit, Siegfried 1960- verfasserin (DE-588)1033566837 (DE-627)741562375 (DE-576)381187314 aut Poggesi, Corrado verfasserin aut Lawlor, Michael W. verfasserin aut Granzier, Henk verfasserin aut Enthalten in Brain Oxford : Oxford Univ. Press, 1878 136(2013), 6, Seite 1718-1731 Online-Ressource (DE-627)269242562 (DE-600)1474117-9 (DE-576)079718728 1460-2156 nnns volume:136 year:2013 number:6 pages:1718-1731 extent:14 Erscheint auch als Druck-Ausgabe Ottenheijm, Coen Adri Charles, 1976 - Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy 2013 (DE-627)1632717085 (DE-576)391846418 https://doi.org/10.1093/brain/awt113 Verlag Resolving-System lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_121 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_374 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2043 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2098 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2145 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2158 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2810 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4346 GBV_ILN_4367 GBV_ILN_4392 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_4753 AR 136 2013 6 1718-1731 14 2013 01 DE-16-250 4108094824 00 --%%-- --%%-- --%%-- --%%-- l01 31-03-22 2013 01 DE-16-250 00 s hd2013 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_15 2013 01 DE-16-250 03 s s_14 2013 01 DE-16-250 04 p (DE-627)1451187556 Labeit, Siegfried 2013 01 DE-16-250 04 k (DE-627)1416467890 Klinik für Anästhesiologie und Operative Intensivmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_12 |
| allfields_unstemmed |
10.1093/brain/awt113 doi (DE-627)1797149970 (DE-599)KXP1797149970 (OCoLC)1341458280 DE-627 ger DE-627 rda eng Ottenheijm, Coen Adri Charles 1976- verfasserin (DE-588)1012497054 (DE-627)661828646 (DE-576)345492889 aut Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit, Corrado Poggesi, Michael W. Lawlor and Henk Granzier 28 May 2013 14 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.03.2022 Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Buck, Danielle verfasserin aut de Winter, Josine M. verfasserin aut Ferrara, Claudia verfasserin aut Piroddi, Nicoletta verfasserin aut Tesi, Chiara verfasserin aut Jasper, Jeffrey R. verfasserin aut Malik, Fady I. verfasserin aut Meng, Hui verfasserin aut Stienen, Ger J. M. verfasserin aut Beggs, Alan H. verfasserin aut Labeit, Siegfried 1960- verfasserin (DE-588)1033566837 (DE-627)741562375 (DE-576)381187314 aut Poggesi, Corrado verfasserin aut Lawlor, Michael W. verfasserin aut Granzier, Henk verfasserin aut Enthalten in Brain Oxford : Oxford Univ. Press, 1878 136(2013), 6, Seite 1718-1731 Online-Ressource (DE-627)269242562 (DE-600)1474117-9 (DE-576)079718728 1460-2156 nnns volume:136 year:2013 number:6 pages:1718-1731 extent:14 Erscheint auch als Druck-Ausgabe Ottenheijm, Coen Adri Charles, 1976 - Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy 2013 (DE-627)1632717085 (DE-576)391846418 https://doi.org/10.1093/brain/awt113 Verlag Resolving-System lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_121 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_374 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2043 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2098 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2145 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2158 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2810 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4346 GBV_ILN_4367 GBV_ILN_4392 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_4753 AR 136 2013 6 1718-1731 14 2013 01 DE-16-250 4108094824 00 --%%-- --%%-- --%%-- --%%-- l01 31-03-22 2013 01 DE-16-250 00 s hd2013 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_15 2013 01 DE-16-250 03 s s_14 2013 01 DE-16-250 04 p (DE-627)1451187556 Labeit, Siegfried 2013 01 DE-16-250 04 k (DE-627)1416467890 Klinik für Anästhesiologie und Operative Intensivmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_12 |
| allfieldsGer |
10.1093/brain/awt113 doi (DE-627)1797149970 (DE-599)KXP1797149970 (OCoLC)1341458280 DE-627 ger DE-627 rda eng Ottenheijm, Coen Adri Charles 1976- verfasserin (DE-588)1012497054 (DE-627)661828646 (DE-576)345492889 aut Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit, Corrado Poggesi, Michael W. Lawlor and Henk Granzier 28 May 2013 14 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.03.2022 Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Buck, Danielle verfasserin aut de Winter, Josine M. verfasserin aut Ferrara, Claudia verfasserin aut Piroddi, Nicoletta verfasserin aut Tesi, Chiara verfasserin aut Jasper, Jeffrey R. verfasserin aut Malik, Fady I. verfasserin aut Meng, Hui verfasserin aut Stienen, Ger J. M. verfasserin aut Beggs, Alan H. verfasserin aut Labeit, Siegfried 1960- verfasserin (DE-588)1033566837 (DE-627)741562375 (DE-576)381187314 aut Poggesi, Corrado verfasserin aut Lawlor, Michael W. verfasserin aut Granzier, Henk verfasserin aut Enthalten in Brain Oxford : Oxford Univ. Press, 1878 136(2013), 6, Seite 1718-1731 Online-Ressource (DE-627)269242562 (DE-600)1474117-9 (DE-576)079718728 1460-2156 nnns volume:136 year:2013 number:6 pages:1718-1731 extent:14 Erscheint auch als Druck-Ausgabe Ottenheijm, Coen Adri Charles, 1976 - Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy 2013 (DE-627)1632717085 (DE-576)391846418 https://doi.org/10.1093/brain/awt113 Verlag Resolving-System lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_121 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_374 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2043 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2098 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2145 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2158 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2810 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4346 GBV_ILN_4367 GBV_ILN_4392 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_4753 AR 136 2013 6 1718-1731 14 2013 01 DE-16-250 4108094824 00 --%%-- --%%-- --%%-- --%%-- l01 31-03-22 2013 01 DE-16-250 00 s hd2013 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_15 2013 01 DE-16-250 03 s s_14 2013 01 DE-16-250 04 p (DE-627)1451187556 Labeit, Siegfried 2013 01 DE-16-250 04 k (DE-627)1416467890 Klinik für Anästhesiologie und Operative Intensivmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_12 |
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10.1093/brain/awt113 doi (DE-627)1797149970 (DE-599)KXP1797149970 (OCoLC)1341458280 DE-627 ger DE-627 rda eng Ottenheijm, Coen Adri Charles 1976- verfasserin (DE-588)1012497054 (DE-627)661828646 (DE-576)345492889 aut Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit, Corrado Poggesi, Michael W. Lawlor and Henk Granzier 28 May 2013 14 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Gesehen am 31.03.2022 Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Buck, Danielle verfasserin aut de Winter, Josine M. verfasserin aut Ferrara, Claudia verfasserin aut Piroddi, Nicoletta verfasserin aut Tesi, Chiara verfasserin aut Jasper, Jeffrey R. verfasserin aut Malik, Fady I. verfasserin aut Meng, Hui verfasserin aut Stienen, Ger J. M. verfasserin aut Beggs, Alan H. verfasserin aut Labeit, Siegfried 1960- verfasserin (DE-588)1033566837 (DE-627)741562375 (DE-576)381187314 aut Poggesi, Corrado verfasserin aut Lawlor, Michael W. verfasserin aut Granzier, Henk verfasserin aut Enthalten in Brain Oxford : Oxford Univ. Press, 1878 136(2013), 6, Seite 1718-1731 Online-Ressource (DE-627)269242562 (DE-600)1474117-9 (DE-576)079718728 1460-2156 nnns volume:136 year:2013 number:6 pages:1718-1731 extent:14 Erscheint auch als Druck-Ausgabe Ottenheijm, Coen Adri Charles, 1976 - Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy 2013 (DE-627)1632717085 (DE-576)391846418 https://doi.org/10.1093/brain/awt113 Verlag Resolving-System lizenzpflichtig Volltext GBV_USEFLAG_U GBV_ILN_2013 ISIL_DE-16-250 SYSFLAG_1 GBV_KXP GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_121 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_374 GBV_ILN_602 GBV_ILN_636 GBV_ILN_647 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2043 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2098 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2145 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2158 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_2810 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4346 GBV_ILN_4367 GBV_ILN_4392 GBV_ILN_4393 GBV_ILN_4700 GBV_ILN_4753 AR 136 2013 6 1718-1731 14 2013 01 DE-16-250 4108094824 00 --%%-- --%%-- --%%-- --%%-- l01 31-03-22 2013 01 DE-16-250 00 s hd2013 2013 01 DE-16-250 01 s (DE-627)1410508463 wissenschaftlicher Artikel (Zeitschrift) 2013 01 DE-16-250 02 s per_15 2013 01 DE-16-250 03 s s_14 2013 01 DE-16-250 04 p (DE-627)1451187556 Labeit, Siegfried 2013 01 DE-16-250 04 k (DE-627)1416467890 Klinik für Anästhesiologie und Operative Intensivmedizin 2013 01 DE-16-250 04 k (DE-627)1416466967 Medizinische Fakultät Heidelberg 2013 01 DE-16-250 04 s (DE-627)1410501914 Verfasser 2013 01 DE-16-250 04 s pos_12 |
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Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy |
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Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy Coen A. C. Ottenheijm, Danielle Buck, Josine M. de Winter, Claudia Ferrara, Nicoletta Piroddi, Chiara Tesi, Jeffrey R. Jasper, Fady I. Malik, Hui Meng, Ger J. M. Stienen, Alan H. Beggs, Siegfried Labeit, Corrado Poggesi, Michael W. Lawlor and Henk Granzier |
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Ottenheijm, Coen Adri Charles Buck, Danielle de Winter, Josine M. Ferrara, Claudia Piroddi, Nicoletta Tesi, Chiara Jasper, Jeffrey R. Malik, Fady I. Meng, Hui Stienen, Ger J. M. Beggs, Alan H. Labeit, Siegfried Poggesi, Corrado Lawlor, Michael W. Granzier, Henk |
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Elektronische Aufsätze |
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deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy |
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Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy |
| abstract |
Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Gesehen am 31.03.2022 |
| abstractGer |
Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Gesehen am 31.03.2022 |
| abstract_unstemmed |
Nebulin—a giant sarcomeric protein—plays a pivotal role in skeletal muscle contractility by specifying thin filament length and function. Although mutations in the gene encoding nebulin (NEB) are a frequent cause of nemaline myopathy, the most common non-dystrophic congenital myopathy, the mechanisms by which mutations in NEB cause muscle weakness remain largely unknown. To better understand these mechanisms, we have generated a mouse model in which Neb exon 55 is deleted (NebΔExon55) to replicate a founder mutation seen frequently in patients with nemaline myopathy with Ashkenazi Jewish heritage. NebΔExon55 mice are born close to Mendelian ratios, but show growth retardation after birth. Electron microscopy studies show nemaline bodies—a hallmark feature of nemaline myopathy—in muscle fibres from NebΔExon55 mice. Western blotting studies with nebulin-specific antibodies reveal reduced nebulin levels in muscle from NebΔExon55 mice, and immunofluorescence confocal microscopy studies with tropomodulin antibodies and phalloidin reveal that thin filament length is significantly reduced. In line with reduced thin filament length, the maximal force generating capacity of permeabilized muscle fibres and single myofibrils is reduced in NebΔExon55 mice with a more pronounced reduction at longer sarcomere lengths. Finally, in NebΔExon55 mice the regulation of contraction is impaired, as evidenced by marked changes in crossbridge cycling kinetics and by a reduction of the calcium sensitivity of force generation. A novel drug that facilitates calcium binding to the thin filament significantly augmented the calcium sensitivity of submaximal force to levels that exceed those observed in untreated control muscle. In conclusion, we have characterized the first nebulin-based nemaline myopathy model, which recapitulates important features of the phenotype observed in patients harbouring this particular mutation, and which has severe muscle weakness caused by thin filament dysfunction. Gesehen am 31.03.2022 |
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