Glucocorticoids are frequently used as anti-inflammatory and immunosuppressive agents. However, high doses and/or prolonged use induce undesired secondary effects such as muscular atrophy. Recently, de novo expression of connexin43 and connexin45 hemichannels (Cx43 HCs and Cx45 HCs, respectively) has been proposed to play a critical role in the mechanism underlying myofiber atrophy induced by dexamethasone (Dex: a synthetic glucocorticoid), but their involvement in specific muscle changes promoted by Dex remains poorly understood. Moreover, treatments that could prevent the undesired effects of glucocorticoids on skeletal muscles remain unknown. In the present work, a 7-day Dex treatment in adult mice was found to induce weight loss and skeletal muscle changes including expression of functional Cx43/Cx45 HCs, elevated atrogin immunoreactivity, atrophy, oxidative stress and mitochondrial dysfunction. All these undesired effects were absent in muscles of mice simultaneously treated with Dex and vitamin E (VitE). Moreover, VitE was found to rapidly inhibit the activity of Cx HCs in freshly isolated myofibers of Dex treated mice. Exposure to alkaline pH induced free radical generation only in HeLa cells expressing Cx43 or Cx45 where Ca2+ was present in the extracellular milieu, response that was prevented by VitE. Besides, VitE and two other anti-oxidant compounds, Tempol and Resveratrol, were found to inhibit Cx43 HCs in HeLa cells transfectants. Thus, we propose that in addition to their intrinsic anti-oxidant potency, some antioxidants could be used to reduce expression and/or opening of Cx HCs and consequently reduce the undesired effect of glucocorticoids on skeletal muscles.
Bibliographical noteFunding Information:
This research was partially funded by the Fondo Nacional de Desarrollo Cient??co y Tecnol?gico (FONDECYT) post-doctoral grant 3160594 (to EB), grant numbers 11160739 (to LAC), 1191329 (to JCS), 1141092 (toTR,LACandJCS),1191329 (toJCS)as well the grant ICM-Econom?a P09-022-FfromtheCentroInterdisciplinario de Neurociencias de Valpara?so (to JCS).
Funding: This research was partially funded by the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) post-doctoral grant 3160594 (to EB), grant numbers 11160739 (to LAC), 1191329 (to JCS), 1141092 (to TR, LAC and JCS), 1191329 (to JCS) as well the grant ICM-Economía P09-022-F from the Centro Interdisciplinario de Neurociencias de Valparaíso (to JCS).
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- Mitochondrial dysfunction
- Muscle atrophy
- Oxidative stress