High Dexamethasone concentration prevents stimulatory effects of TNF-{alpha} and LPS on the IL-6 secretion from the precursors of human muscle regeneration

Laboratory for Molecular Neurobiology, Institute of Pathophysiology, School of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia.
AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.11). 12/2006; 291(6):R1651-6. DOI: 10.1152/ajpregu.00020.2006
Source: PubMed


A frequent finding in patients surviving critical illness myopathy is chronic muscle dysfunction. Its pathogenesis is mostly unknown; one explanation could be that muscle regeneration, which normally follows myopathy, is insufficient in these patients because of a high glucocorticoid level in their blood. Glucocorticoids can prevent stimulatory effects of proinflammatory factors on the interleukin (IL)-6 secretion, diminishing in this way the autocrine and paracrine IL-6 actions known to stimulate proliferation at the earliest, myoblast stage of muscle formation. To test this hypothesis, we compared the effects of major proinflammatory agents [tumor necrosis factor (TNF)-alpha and endotoxin lipopolysaccharide (LPS)] on the IL-6 secretion from the muscle precursors and then studied the influence of dexamethasone (Dex) on these effects. Mononuclear myoblasts, which still proliferate, were compared with myotubes in which this capacity is already lost. For correct interpretation of results, cultures were examined for putative apoptosis and necrosis. We found that constitutive secretion of IL-6 did not differ significantly between myoblasts and myotubes; however, the TNF-alpha- and LPS-stimulated IL-6 release was more pronounced (P < 0.001) in myoblasts. Dex, applied at the 0.1-100 nM concentration range, prevented constitutive and TNF-alpha- and LPS-stimulated IL-6 release at both developmental stages but only at high concentration (P < 0.01). Although there are still missing links to it, our results support the concept that high concentrations of glucocorticoids, met in critically ill patients, prevent TNF-alpha- and LPS-stimulated IL-6 secretion. This results in reduced IL-6-mediated myoblast proliferation, leading to the reduced final mass of the regenerated muscle.

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    • "The reduction in Myogenin levels, observed in the DX + n-3 group, is consistent with results from other studies showing that dexamethasone induces many unfavorable conditions to myogenesis, partially through Myogenin inhibition [54, 55], but we did not observe a similar increase in DX group. Another study showed that dexamethasone prevents the formation of TNF-alpha and the release of lipopolysaccharide-stimulated IL-6, which influences myoblast proliferation [56]. However, no change was demonstrated in transcription factors related to myogenesis in DX group; a decrease was observed only in DX + n-3 group compared to the CT group. "
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    ABSTRACT: Corticosteroids cause muscle atrophy by acting on proteasomal and lysosomal systems and by affecting pathways related to muscular trophysm, such as the IGF-1/PI-3k/Akt/mTOR. Omega-3 fatty acid (n-3) has been used beneficially to attenuate muscle atrophy linked to sepsis and cachexia; however, its effect on dexamethasone-induced muscle atrophy has not been evaluated. Objectives. We evaluated whether n-3 supplementation could mitigate the development of dexamethasone-induced muscle atrophy. Methods. Two groups of Wistar rats were orally supplemented with n-3 or vehicle solution for 40 days. In the last 10 days, dexamethasone, or saline solution, was administrated establishing four groups: control, dexamethasone, n-3, and dexamethasone + n-3. The cross-sectional areas of muscle fibers, gene expression (MyoD, Myogenin, MuRF-1, and Atrogin-1), and protein expression (Akt, GSK3β, FOXO3a, and mTOR) were assessed. Results. Dexamethasone induced a significant loss in body and muscle weight, atrophy in type 2B fibers, and decreased expression of P-Akt, P-GSK3β, and P-FOXO3a. N-3 supplementation did not attenuate the negative effects of dexamethasone on skeletal muscle; instead, it caused atrophy in type 1, 2A, reduced the expression of Myogenin, and increased the expression of Atrogin-1. Conclusion. Food supplements containing n-3 are usually healthful, but they may potentiate some of the side effects of glucocorticoids.
    BioMed Research International 05/2014; 2014(17):961438. DOI:10.1155/2014/961438 · 1.58 Impact Factor
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    • "This suggests that IL-6 secretion by both MPCs and M1 macrophages facilitates the regeneration process. Both IL-1β and TNF-α have been shown to increase IL-6 expression and release, as well as reduce myogenic differentiation [28], [34]–[36]. However, the mechanism of IL-1β induced IL-6 expression, and the relationship between TNF-α, IL-1β, and IL-6 during the critical stages of MPC proliferation have yet to be resolved. "
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    ABSTRACT: Skeletal muscle satellite cell function is largely dictated by the surrounding environment following injury. Immune cell infiltration dominates the extracellular space in the injured area, resulting in increased cytokine concentrations. While increased pro-inflammatory cytokine expression has been previously established in the first 3 days following injury, less is known about the time course of cytokine expression and the specific mechanisms of cytokine induced myoblast function. Therefore, the expression of IL-1β and IL-6 at several time points following injury, and their effects on myoblast proliferation, were examined. In order to do this, skeletal muscle was injured using barium chloride in mice and tissue was collected 1, 5, 10, and 28 days following injury. Mechanisms of cytokine induced proliferation were determined in cell culture using both primary and C2C12 myoblasts. It was found that there is a ∼20-fold increase in IL-1β (p≤0.05) and IL-6 (p = 0.06) expression 5 days following injury. IL-1β increased proliferation of both primary and C2C12 cells ∼25%. IL-1β stimulation also resulted in increased NF-κB activity, likely contributing to the increased proliferation. These data demonstrate for the first time that IL-1β alone can increase the mitogenic activity of primary skeletal muscle satellite cells and offer insight into the mechanisms dictating satellite cell function following injury.
    PLoS ONE 03/2014; 9(3):e92363. DOI:10.1371/journal.pone.0092363 · 3.23 Impact Factor
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    • "Levels of secreted IL-6 in the culture supernatant collected from the cultures 24-h after exposure to irradiation were measured using an Enzyme-Linked ImmunoSorbent Assay (ELISA) kit (Endogen, Rockford, USA), according to the manufacturer’s instructions and as described previously.17 IL-6 levels were calculated from concentrations of IL-6 measured in supernatants in each well. "
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    ABSTRACT: Long term effects of different doses of ionizing radiation on human skeletal muscle myoblast proliferation, cytokine signalling and stress response capacity were studied in primary cell cultures. Human skeletal muscle myoblasts obtained from muscle biopsies were cultured and irradiated with a Darpac 2000 X-ray unit at doses of 4, 6 and 8 Gy. Acute effects of radiation were studied by interleukin - 6 (IL-6) release and stress response detected by the heat shock protein (HSP) level, while long term effects were followed by proliferation capacity and cell death. Compared with non-irradiated control and cells treated with inhibitor of cell proliferation Ara C, myoblast proliferation decreased 72 h post-irradiation, this effect was more pronounced with increasing doses. Post-irradiation myoblast survival determined by measurement of released LDH enzyme activity revealed increased activity after exposure to irradiation. The acute response of myoblasts to lower doses of irradiation (4 and 6 Gy) was decreased secretion of constitutive IL-6. Higher doses of irradiation triggered a stress response in myoblasts, determined by increased levels of stress markers (HSPs 27 and 70). Our results show that myoblasts are sensitive to irradiation in terms of their proliferation capacity and capacity to secret IL-6. Since myoblast proliferation and differentiation are a key stage in muscle regeneration, this effect of irradiation needs to be taken in account, particularly in certain clinical conditions.
    Radiology and Oncology 12/2013; 47(4):376-381. DOI:10.2478/raon-2013-0058 · 1.91 Impact Factor
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