Vitamin E Blocks Connexin Hemichannels and Prevents Deleterious Effects of Glucocorticoid Treatment on Skeletal Muscles

Abstract

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.

Blockade of Hemichannels Normalizes the Differentiation Fate of Myoblasts and Features of Skeletal Muscles from Dysferlin-Deficient Mice

“…However, this putative effect might be canceled by the inhibitory effect of boldine on nicotinic receptors as it has been demonstrated in the mouse phrenic nerve-diaphragm [ 43 ]. In addition, the anti-oxidant effect of boldine [ 44 ] can be reinterpreted since several antioxidant compounds first block Cx HCs permeable to Ca 2+ [ 45 ], which activates several intracellular metabolic pathways that generate reactive oxygen substances. Thus, it can be predicted that boldine’s first effect is to impede Ca 2+ entrance and consequently prevents the generation of free radicals rather than acting directly as an anti-oxidant compound [ 45 ].…”

“…In addition, the anti-oxidant effect of boldine [ 44 ] can be reinterpreted since several antioxidant compounds first block Cx HCs permeable to Ca 2+ [ 45 ], which activates several intracellular metabolic pathways that generate reactive oxygen substances. Thus, it can be predicted that boldine’s first effect is to impede Ca 2+ entrance and consequently prevents the generation of free radicals rather than acting directly as an anti-oxidant compound [ 45 ]. Therefore, and despite the pleiotropic effect of boldine at molecular components of the neuromuscular junction, the outcome of the boldine treatment might mainly reflect its action as a Cx HC inhibitor.…”

Nutrients against Glucocorticoid-Induced Muscle Atrophy

“…Vitamins play multi-functional roles in skeletal muscle metabolism. It has been reported that the vitamin-mediated antioxidative capacity and regulation of target genes associated with the functions of skeletal muscle play beneficial roles in steroid-induced muscle dysfunctions ( Table 3 ) [ 61 , 62 ].…”

“…A recent study revealed that de novo expression of connexin43 and connexin45 hemichannels were involved in dexamethasone-induced muscle atrophy. When the outcomes of vitamin E supplementation on dexamethasone-mediated myotube atrophy were studied, dexamethasone increased the expression of connexin43 and connexin45, atrogin-1 immunoreactivity, oxidative stress, mitochondrial dysfunction, and atrophy in the skeletal muscle, whereas vitamin E supplementation reversed these characteristics [ 62 ]. Similarly, vitamin E suppressed connexin43/45 hemichannel activity in freshly isolated myofibers of dexamethasone-treated mice, suggesting that vitamin E is effective in relieving steroid-induced muscle atrophy at least partly by reducing connexin hemichannel activity [ 62 ].…”

Gap Junctions and Hemichannels Composed of Connexins and Pannexins Mediate the Secondary Brain Injury Following Intracerebral Hemorrhage

“…Moreover, oxidation products were shown to increase hemichannel activity whilst reducing GJIC [ 60 ]. Thus, antioxidant therapy may inhibit hemichannel activity [ 61 ] and attenuate apoptosis [ 62 ]. As mentioned above, Cx43 gap junctions between astrocytes essentially retain homeostasis.…”