Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness.
Many mutations in the skeletal muscle α-actin gene (ACTA1) lead to muscle weakness and nemaline myopathy. Despite increasing clinical and scientific interest, the molecular and cellular pathogenesis of weakness remains unclear. Therefore, in the present study, we aimed at unraveling these mechanisms...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3447773?pdf=render |
| _version_ | 1818851170962112512 |
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| author | Julien Ochala Gianina Ravenscroft Nigel G Laing Kristen J Nowak |
| author_facet | Julien Ochala Gianina Ravenscroft Nigel G Laing Kristen J Nowak |
| author_sort | Julien Ochala |
| collection | DOAJ |
| description | Many mutations in the skeletal muscle α-actin gene (ACTA1) lead to muscle weakness and nemaline myopathy. Despite increasing clinical and scientific interest, the molecular and cellular pathogenesis of weakness remains unclear. Therefore, in the present study, we aimed at unraveling these mechanisms using muscles from a transgenic mouse model of nemaline myopathy expressing the ACTA1 Asp286Gly mutation. We recorded and analyzed the mechanics of membrane-permeabilized single muscle fibers. We also performed molecular energy state computations in the presence or absence of Asp286Gly. Results demonstrated that during contraction, the Asp286Gly acts as a "poison-protein" and according to the computational analysis it modifies the actin-actin interface. This phenomenon is likely to prevent proper myosin cross-bridge binding, limiting the fraction of actomyosin interactions in the strong binding state. At the cell level, this decreases the force-generating capacity, and, overall, induces muscle weakness. To counterbalance such negative events, future potential therapeutic strategies may focus on the inappropriate actin-actin interface or myosin binding. |
| first_indexed | 2024-12-19T07:00:47Z |
| format | Article |
| id | doaj.art-fc7138660c49426b930bf1dfcd7344fb |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T07:00:47Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-fc7138660c49426b930bf1dfcd7344fb2022-12-21T20:31:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0179e4592310.1371/journal.pone.0045923Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness.Julien OchalaGianina RavenscroftNigel G LaingKristen J NowakMany mutations in the skeletal muscle α-actin gene (ACTA1) lead to muscle weakness and nemaline myopathy. Despite increasing clinical and scientific interest, the molecular and cellular pathogenesis of weakness remains unclear. Therefore, in the present study, we aimed at unraveling these mechanisms using muscles from a transgenic mouse model of nemaline myopathy expressing the ACTA1 Asp286Gly mutation. We recorded and analyzed the mechanics of membrane-permeabilized single muscle fibers. We also performed molecular energy state computations in the presence or absence of Asp286Gly. Results demonstrated that during contraction, the Asp286Gly acts as a "poison-protein" and according to the computational analysis it modifies the actin-actin interface. This phenomenon is likely to prevent proper myosin cross-bridge binding, limiting the fraction of actomyosin interactions in the strong binding state. At the cell level, this decreases the force-generating capacity, and, overall, induces muscle weakness. To counterbalance such negative events, future potential therapeutic strategies may focus on the inappropriate actin-actin interface or myosin binding.http://europepmc.org/articles/PMC3447773?pdf=render |
| spellingShingle | Julien Ochala Gianina Ravenscroft Nigel G Laing Kristen J Nowak Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness. PLoS ONE |
| title | Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness. |
| title_full | Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness. |
| title_fullStr | Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness. |
| title_full_unstemmed | Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness. |
| title_short | Nemaline myopathy-related skeletal muscle α-actin (ACTA1) mutation, Asp286Gly, prevents proper strong myosin binding and triggers muscle weakness. |
| title_sort | nemaline myopathy related skeletal muscle α actin acta1 mutation asp286gly prevents proper strong myosin binding and triggers muscle weakness |
| url | http://europepmc.org/articles/PMC3447773?pdf=render |
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