Myofibers deficient in connexins 43 and 45 expression protect mice from skeletal muscle and systemic dysfunction promoted by a dysferlin mutation
Copyright © 2020 Elsevier B.V. All rights reserved..
Dysferlinopathy is a genetic human disease caused by mutations in the gene that encodes the dysferlin protein (DYSF). Dysferlin is believed to play a relevant role in cell membrane repair. However, in dysferlin-deficient (blAJ) mice (a model of dysferlinopathies) the recovery of the membrane resealing function by means of the expression of a mini-dysferlin does not arrest progressive muscular damage, suggesting the participation of other unknown pathogenic mechanisms. Here, we show that proteins called connexins 39, 43 and 45 (Cx39, Cx43 and Cx45, respectively) are expressed by blAJ myofibers and form functional hemichannels (Cx HCs) in the sarcolemma. At rest, Cx HCs increased the sarcolemma permeability to small molecules and the intracellular Ca2+ signal. In addition, skeletal muscles of blAJ mice showed lipid accumulation and lack of dysferlin immunoreactivity. As sign of extensive damage and atrophy, muscles of blAJ mice presented elevated numbers of myofibers with internal nuclei, increased number of myofibers with reduced cross-sectional area and elevated creatine kinase activity in serum. In agreement with the extense muscle damage, mice also showed significantly low motor performance. We generated blAJ mice with myofibers deficient in Cx43 and Cx45 expression and found that all above muscle and systemic alterations were absent, indicating that these two Cxs play a critical role in a novel pathogenic mechanism of dysfernolophaties, which is discussed herein. Therefore, Cx HCs could constitute an attractive target for pharmacologic treatment of dyferlinopathies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1866 |
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| Enthalten in: |
Biochimica et biophysica acta. Molecular basis of disease - 1866(2020), 8 vom: 01. Aug., Seite 165800 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fernández, Gabriela [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.01.2021 Date Revised 04.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbadis.2020.165800 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM30890236X |
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| 100 | 1 | |a Fernández, Gabriela |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Myofibers deficient in connexins 43 and 45 expression protect mice from skeletal muscle and systemic dysfunction promoted by a dysferlin mutation |
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| 500 | |a Date Revised 04.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier B.V. All rights reserved. | ||
| 520 | |a Dysferlinopathy is a genetic human disease caused by mutations in the gene that encodes the dysferlin protein (DYSF). Dysferlin is believed to play a relevant role in cell membrane repair. However, in dysferlin-deficient (blAJ) mice (a model of dysferlinopathies) the recovery of the membrane resealing function by means of the expression of a mini-dysferlin does not arrest progressive muscular damage, suggesting the participation of other unknown pathogenic mechanisms. Here, we show that proteins called connexins 39, 43 and 45 (Cx39, Cx43 and Cx45, respectively) are expressed by blAJ myofibers and form functional hemichannels (Cx HCs) in the sarcolemma. At rest, Cx HCs increased the sarcolemma permeability to small molecules and the intracellular Ca2+ signal. In addition, skeletal muscles of blAJ mice showed lipid accumulation and lack of dysferlin immunoreactivity. As sign of extensive damage and atrophy, muscles of blAJ mice presented elevated numbers of myofibers with internal nuclei, increased number of myofibers with reduced cross-sectional area and elevated creatine kinase activity in serum. In agreement with the extense muscle damage, mice also showed significantly low motor performance. We generated blAJ mice with myofibers deficient in Cx43 and Cx45 expression and found that all above muscle and systemic alterations were absent, indicating that these two Cxs play a critical role in a novel pathogenic mechanism of dysfernolophaties, which is discussed herein. Therefore, Cx HCs could constitute an attractive target for pharmacologic treatment of dyferlinopathies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Calcium ion | |
| 650 | 4 | |a Fat infiltration | |
| 650 | 4 | |a Membrane permeability | |
| 650 | 4 | |a Muscular dystrophy | |
| 650 | 4 | |a Muscular performance | |
| 650 | 7 | |a Connexin 43 |2 NLM | |
| 650 | 7 | |a Connexins |2 NLM | |
| 650 | 7 | |a Dysf protein, mouse |2 NLM | |
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| 650 | 7 | |a Calcium |2 NLM | |
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| 700 | 1 | |a Arias-Bravo, Guisselle |e verfasserin |4 aut | |
| 700 | 1 | |a Bevilacqua, Jorge A |e verfasserin |4 aut | |
| 700 | 1 | |a Castillo-Ruiz, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Caviedes, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Sáez, Juan C |e verfasserin |4 aut | |
| 700 | 1 | |a Cea, Luis A |e verfasserin |4 aut | |
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