De novo expression of functional connexins 43 and 45 hemichannels increases sarcolemmal permeability of skeletal myofibers during endotoxemia

Luis, A.; Balboa, Elisa; Vargas, Aníbal A.; Puebla, Carlos; Brañes, María C.; Escamilla, Rosalba; Regueira, Tomás; Sáez, Juan C.

doi:10.1016/j.bbadis.2019.06.014

Cited by 19 publications

(19 citation statements)

References 46 publications

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“…The above interpretation is also in agreement with our findings since myofibers of mice simultaneous treated with VitE and Dex did not present significant Cx43 and Cx45 immunoreactivity and the acute application of VitE blocked Cx HCs in freshly isolated myofibers of Dex treated mice or HeLa cells transfected with Cxs and exposed to divalent cation solution. Similar results have been previously obtained in Cx43 and Cx45 expression during endotoxemia and treatment with boldine that rapidly blocked Cxs and completely abrogated Cx45 and Cx43 immunoreactivity [36].…”

Section: Discussionsupporting

confidence: 90%

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

Balboa

Saavedra

Luis

et al. 2020

IJMS

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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.

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Section: Discussionsupporting

confidence: 90%

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

Balboa

Saavedra

Luis

et al. 2020

IJMS

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“…Treatment with IL-1β/TNF-α has been proved to increase Cx43 hemichannel activity in diverse cell types including astrocytes, myofibers, retinal epithelium and endothelial cells [19,[41][42][43][44]. In cultured astrocytes, 24 h treatment with a mixture of these two cytokines (10 ng/mL for each) enhances Etd uptake and current unitary events linked to the opening of Cx43 hemichannels [42].…”

Section: Il-1β Plus Tnf-α Modulates the Permeation Of Permeability Tracers Through Astroglial Cx43 Hemichannels Depending On The Permeantmentioning

confidence: 99%

Permeation of Molecules through Astroglial Connexin 43 Hemichannels Is Modulated by Cytokines with Parameters Depending on the Permeant Species

Sáez

Vargas

Hernández

et al. 2020

IJMS

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Recent studies indicate that connexin hemichannels do not act as freely permeable non-selective pores, but they select permeants in an isoform-specific manner with cooperative, competitive and saturable kinetics. The aim of this study was to investigate whether the treatment with a mixture of IL-1β plus TNF-α, a well-known pro-inflammatory condition that activates astroglial connexin 43 (Cx43) hemichannels, could alter their permeability to molecules. We found that IL-1β plus TNF-α left-shifted the dye uptake rate vs. dye concentration relationship for Etd and 2-NBDG, but the opposite took place for DAPI or YO-PRO-1, whereas no alterations were observed for Prd. The latter modifications were accompanied of changes in Kd (Etd, DAPI, YO-PRO-1 or 2-NBDG) and Hill coefficients (Etd and YO-PRO-1), but not in alterations of Vmax. We speculate that IL-1β plus TNF-α may distinctively affect the binding sites to permeants in astroglial Cx43 hemichannels rather than their number in the cell surface. Alternatively, IL-1β plus TNF-α could induce the production of endogenous permeants that may favor or compete for in the pore-lining residues of Cx43 hemichannels. Future studies shall elucidate whether the differential ionic/molecule permeation of Cx43 hemichannels in astrocytes could impact their communication with neurons in the normal and inflamed nervous system.

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“…As muscle differentiation proceeds and muscle fibers begin to be innervated, the connexins expressed in developing muscle, Cx43 and 45, are downregulated and are not expressed at the sarcolemma of healthy adult skeletal muscle fibers (26, 34). When exposed to insults that may lead to muscle atrophy, such as a sciatic nerve transection (27), dexamethasone administration (28) and endotoxemia/sepsis (35), CxHCs reappear on the sarcolemma of fast-twitch muscle fibers. Appearance of sarcolemmal CxHC lowers membrane potential (30) and activates the inflammasome (27).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, disuse from hindlimb unloading does not result in increased CxHC appearance (30), demonstrating additional mechanisms outside of disuse drive CxHC cellular translocation. Conditionally knocking out Cx43 and 45 in skeletal muscle can reduce muscle atrophy following denervation by a sciatic nerve transection (27), and inhibiting their activity with molecular interventions has positive effects on muscle health (29, 30, 35, 36). A promising molecule is boldine, an alkaloid derived from the Chilean boldo tree ( Peumus boldus ).…”

Section: Introductionmentioning

confidence: 99%

“…A promising molecule is boldine, an alkaloid derived from the Chilean boldo tree ( Peumus boldus ). Boldine can inhibit CxHC activity without blocking GJ function (37), and has been shown to prevent sepsis-induced increases in cytosolic calcium concentrations and cytokine-induced small molecule dye uptake in isolated muscle fibers (35). Furthermore, 8 wks of boldine treatment in mice with dysferlinopathy improved motor function, reduced skeletal muscle fat accumulation and rescued aberrant dysferlin protein expression (29).…”

Section: Introductionmentioning

confidence: 99%

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Assessing the impact of boldine on the gastrocnemius using multiomic profiling at 7 and 28 days post-complete spinal cord injury in young male mice

Potter¹,

Toro

Harlow³

et al. 2022

Preprint

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Spinal cord injury (SCI) results in rapid muscle loss. The mechanisms of muscle atrophy have been well-described but there is limited information specific to SCI. Exogenous molecular interventions to slow muscle atrophy in severe-to-complete SCI have been relatively ineffective and the wide-ranging physiologic response to SCI requires the search for novel therapeutic targets. Connexin hemichannels (CxHC) allow non-selective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising pre-clinical results in slowing atrophy during sepsis and dysferlinopathy. We administered 50 mg/kg/d of boldine to spinal cord transected mice beginning at day 3 post-injury. Tissue was collected 7 and 28 d post-injury and the gastrocnemius used for multiomic profiling. Boldine did not prevent body or muscle mass loss but attenuatee SCI-induced changes in the abundance of proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 d post-SCI. SCI resulted in the differential expression of ~7,700 and ~2,000 genes at 7 and 28 d, respectively, compared to sham animals, with enrichment for pathways associated with ribosome biogenesis, translation and oxidative phosphorylation. Boldine altered the expression of ~150 genes at 7 d and ~110 genes at 28 d post-SCI. Methylation analyses highlighted distinct patterns at both 7 and 28 d following SCI both with and without boldine. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it preserved or attenuated SCI-induced changes across the metabolome, transcriptome and methylome.

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De novo expression of functional connexins 43 and 45 hemichannels increases sarcolemmal permeability of skeletal myofibers during endotoxemia

Cited by 19 publications

References 46 publications

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

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

Permeation of Molecules through Astroglial Connexin 43 Hemichannels Is Modulated by Cytokines with Parameters Depending on the Permeant Species

Assessing the impact of boldine on the gastrocnemius using multiomic profiling at 7 and 28 days post-complete spinal cord injury in young male mice

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