Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels
Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorti...
| Authors: | ; ; ; ; ; ; ; |
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| Format: | Article |
| Status: | Published version |
| Publication date: | 2016 |
| Country: | Chile |
| Institution: | Agencia Nacional de Investigación y Desarrollo |
| Repository: | Articulos_ANID |
| Language: | English |
| OAI Identifier: | oai:repositorio.anid.cl:10533/252556 |
| Online Access: | https://hdl.handle.net/10533/252556 |
| Access Level: | Open access |
| _version_ | 1879188265278373888 |
|---|---|
| author | Cea, Luis A |
| author2 | Balboa, Elisa Puebla, Carlos Vargas-Ríos, Aníbal Antonio Cisterna-Irrazabal, Bruno Alejandro Escamilla, Rosalba Regueira, Tomas Sáez-Carreño, Juan Carlos |
| author2_role | author author author author author author author |
| author_browse | Balboa, Elisa Cea, Luis A Cisterna-Irrazabal, Bruno Alejandro Escamilla, Rosalba Puebla, Carlos Regueira, Tomas Sáez-Carreño, Juan Carlos Vargas-Ríos, Aníbal Antonio |
| author_facet | Cea, Luis A Balboa, Elisa Puebla, Carlos Vargas-Ríos, Aníbal Antonio Cisterna-Irrazabal, Bruno Alejandro Escamilla, Rosalba Regueira, Tomas Sáez-Carreño, Juan Carlos |
| author_role | author |
| collection | Articulos_ANID |
| description | Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, on control (Cx43(fl/fl)Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre) skeletal myofibers. Myofibers of Cx43(fl/fl)Cx45(fl/fl) mice treated with DEX (5 h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panxi, P2X7 receptor and TRPV2). After 5 h DEX treatment in vivo, myofibers of Cx43(fl/fl)Cx45(fl/fl) mice showed Evans blue uptake, which was absent in myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Similar results were obtained in vitro using ethidium as an HC permeability probe, and DEX-induced dye uptake in control myofibers was blocked by P2X(7) receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca2+ signal and a reduction in resting membrane potential in Cx43(fl/fl)Cx45(fl/fl) myofibers, changes that were not elicited by myofibers deficient in Cx43/Cx45 expression. Moreover, treatment with DEX induced NF kappa B activation and increased mRNA levels of TNF-alpha. in control but not in Cx43(fl/fl)Cx45(fl/fl) expression-deficient myofibers. Finally, a prolonged DEX treatment (7 days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43(fl/fl)Cx45(fl/fl) myofibers, but these parameters remained unaffected in Cx43(fl/fl)Cx45(fl/fl):Myo-Cre myofibers. Therefore, DEX-induced expression of Cx43 and Cx45 plays a critical role in early sarcolemma changes that lead to atrophy. Consequently, this side effect of chronic glucocorticoid treatment might be avoided by co-administration with a Cx HC blocker. (C) 2016 Elsevier B.V. All rights reserved. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | CL_acfe9cfc394b4abd4005dcc2560d6c99 |
| institution | Agencia Nacional de Investigación y Desarrollo |
| instname_str | Agencia Nacional de Investigación y Desarrollo |
| language | eng |
| network_acronym_str | CL |
| network_name_str | Chile |
| oai_identifier_str | oai:repositorio.anid.cl:10533/252556 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| reponame_str | Articulos_ANID |
| spelling | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE Cea, Luis A Balboa, Elisa Puebla, Carlos Vargas-Ríos, Aníbal Antonio Cisterna-Irrazabal, Bruno Alejandro Escamilla, Rosalba Regueira, Tomas Sáez-Carreño, Juan Carlos Long-term treatment with high glucocorticoid doses induces skeletal muscle atrophy. However, the molecular mechanism of such atrophy remains unclear. We evaluated the possible involvement of connexin-based hemichannels (Cx HCs) in muscle atrophy induced by dexamethasone (DEX), a synthetic glucocorticoid, on control (Cx43(fl/fl)Cx45(fl/fl)) and Cx43/Cx45 expression-deficient (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre) skeletal myofibers. Myofibers of Cx43(fl/fl)Cx45(fl/fl) mice treated with DEX (5 h) expressed several proteins that form non-selective membrane channels (Cx39, Cx43, Cx45, Panxi, P2X7 receptor and TRPV2). After 5 h DEX treatment in vivo, myofibers of Cx43(fl/fl)Cx45(fl/fl) mice showed Evans blue uptake, which was absent in myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Similar results were obtained in vitro using ethidium as an HC permeability probe, and DEX-induced dye uptake in control myofibers was blocked by P2X(7) receptor inhibitors. DEX also induced a significant increase in basal intracellular Ca2+ signal and a reduction in resting membrane potential in Cx43(fl/fl)Cx45(fl/fl) myofibers, changes that were not elicited by myofibers deficient in Cx43/Cx45 expression. Moreover, treatment with DEX induced NF kappa B activation and increased mRNA levels of TNF-alpha. in control but not in Cx43(fl/fl)Cx45(fl/fl) expression-deficient myofibers. Finally, a prolonged DEX treatment (7 days) increased atrogin-1 and Murf-1 and reduced the cross sectional area of Cx43(fl/fl)Cx45(fl/fl) myofibers, but these parameters remained unaffected in Cx43(fl/fl)Cx45(fl/fl):Myo-Cre myofibers. Therefore, DEX-induced expression of Cx43 and Cx45 plays a critical role in early sarcolemma changes that lead to atrophy. Consequently, this side effect of chronic glucocorticoid treatment might be avoided by co-administration with a Cx HC blocker. (C) 2016 Elsevier B.V. All rights reserved. Regular 2015 FONDECYT 1150291 WOS:000382413300005 https://hdl.handle.net/10533/252556 |
| spellingShingle | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels Cea, Luis A |
| status_str | publishedVersion |
| title | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels |
| title_full | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels |
| title_fullStr | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels |
| title_full_unstemmed | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels |
| title_short | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels |
| title_sort | Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels |
| url | https://hdl.handle.net/10533/252556 |