Glucocorticoid-induced muscle atrophy is characterized by fast-twitch or type II muscle fiber atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. ...Muscle proteolysis, in particular through the ubiquitin- proteasome system (UPS), is considered to play a major role in the catabolic action of glucocorticoids. The stimulation by glucocorticoids of the UPS is mediated through the increased expression of several atrogenes ('genes involved in atrophy'), such as atrogin-1 and MuRF-1, two ubiquitin ligases involved in the targeting of protein to be degraded by the proteasome machinery. Glucocorticoids also exert an anti-anabolic action by blunting muscle protein synthesis. These changes in protein turnover may result from changes in the production of two growth factors which control muscle mass, namely IGF-I and myostatin respectively anabolic and catabolic toward the skeletal muscle. The decreased production of IGF-I as well as the increased production of myostatin have been both demonstrated to contribute to the muscle atrophy caused by glucocorticoids. At the molecular level, IGF-I antagonizes the catabolic action of glucocorticoids by inhibiting, through the PI3-kinase/Akt pathway, the activity of the transcription factor FOXO, a major switch for the stimulation of several atrogenes. These recent progress in the understanding of the glucocorticoid-induced muscle atrophy should allow to define new therapies aiming to minimize this myopathy. Promising new therapeutic approaches for treating glucocorticoid-induced muscle atrophy are also presented in this review.
Glucocorticoid-induced skeletal muscle atrophy Schakman, O.; Kalista, S.; Barbé, C. ...
The international journal of biochemistry & cell biology,
10/2013, Letnik:
45, Številka:
10
Journal Article
Recenzirano
Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating ...glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes (“genes involved in atrophy”), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy.
This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
Abstract
Fourth-generation ‘pod’ e-cigarette devices have been driven by technological advances in electronic atomization of the e-liquid. Use of microporous ceramic as a wicking material improves ...heating efficiency, but how it affects the chemical emissions of these devices is unclear. We assessed the emissions of a pod e-cigarette with innovative ceramic wick-based technology and two flavoured e-liquids containing nicotine lactate and nicotine benzoate (57 and 18 mg mL
−1
nicotine, respectively). Among the studied harmful and potentially harmful constituents (HPHCs) listed by the US FDA and/or WHO TobReg, only 5 (acetone, acetaldehyde, formaldehyde, naphthalene and nornicotine) were quantified at levels of 0.14 to 100 ng puff
−1
. In the combustible cigarette (Kentucky reference 1R6F), levels were from 0.131 to 168 µg puff
−1
. Nicotine levels ranged 0.10–0.32 mg puff
−1
across the 3 study products. From the 19 proposed HPHCs specifically of concern in e-cigarettes, only 3 (glycerol, isoamyl acetate and propylene glycol) were quantified. The low/undetectable levels of HPHCs reflect not only the optimal operating conditions of the e-cigarette, including an efficient supply of e-liquid by the ceramic wick without overheating, but also the potential of the e-cigarettes to be used as an alternative to combustible cigarettes.
Glucocorticoids mediate muscle atrophy in many catabolic states. Myostatin expression, a negative regulator of muscle growth, is increased by glucocorticoids and myostatin overexpression is ...associated with lower muscle mass. This suggests that myostatin is required for the catabolic effects of glucocorticoids. We therefore investigated whether myostatin gene disruption could prevent muscle atrophy caused by glucocorticoids. Male myostatin knockout (KO) and wild-type mice were subjected to dexamethasone treatment (1 mg/kg·d for 10 d or 5 mg/kg·d for 4 d). In wild-type mice, daily administration of low-dose dexamethasone for 10 d resulted in muscle atrophy (tibialis anterior: −15%; gastrocnemius: −13%; P < 0.01) due to 15% decrease in the muscle fiber cross-sectional area (1621 ± 31 vs. 1918 ± 64 μm2, P < 0.01). In KO mice, there was no reduction of muscle mass nor fiber cross-sectional area after dexamethasone treatment. Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity. In contrast, the mRNA of these enzymes and the proteasomal activity were not significantly affected by dexamethasone in KO mice. Muscle IGF-I mRNA was paradoxically decreased in KO mice (−35%, P < 0.05); this was associated with a potentially compensatory increase of IGF-II expression in both saline and dexamethasone-treated KO mice (2-fold, P < 0.01). In conclusion, our results show that myostatin deletion prevents muscle atrophy in glucocorticoid-treated mice, by blunting the glucocorticoid-induced enhanced proteolysis, and suggest an important role of myostatin in muscle atrophy caused by glucocorticoids.
Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved ...are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.
There are very few studies on the long-term outcome of children and adolescents with ADHD-combined type in Europe. The objective of the present study is to assess the 6-year outcome (including ...pharmacological treatment) of a large cohort of participants with ADHD-combined type (
N
= 347, mean age 11.4 years) in late adolescence and early adulthood. At study entry and follow-up (mean age 17.4 years), participants were comprehensively assessed on ADHD and comorbid disorders by structured psychiatric interviews and multi-informant questionnaires. Overall functioning was assessed by the Children’s Global Assessment Scale. The retention rate was 75.6 %. The majority of participants (86.5 %) persisted in a DSM-5 ADHD diagnosis, 8.4 % had a subthreshold diagnosis, and 5.1 % remitted from the disorder at follow-up. Comorbidities decreased strongly; oppositional defiant disorder: 58 > 31 %, conduct disorder: 19 > 7 %. At follow-up, mood- and anxiety disorders were virtually non-existent following strict criteria (1–3 %). Percentage of children having had pharmacological treatment at any time increased from 79 to 91 %. On the Children’s Global Assessment Scale, 48.5 % of participants were still functionally impaired at follow-up. Parental ADHD, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline positively predicted current ADHD symptom severity (
R
2
= 20.9 %). Younger baseline age, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline were positively associated with poorer overall functioning (
R
2
= 17.8 %). Pharmacological treatment had no (beneficial) impact on either ADHD symptom severity or overall functioning. Results confirm that ADHD is largely persistent into late adolescence with severity and family history for the disorder as important risk factors.
True polar wander (TPW), or planetary reorientation, is well documented for other planets and moons and for Earth at present day with satellites, but testing its prevalence in Earth's past is ...complicated by simultaneous motions due to plate tectonics. Debate has surrounded the existence of Late Cretaceous TPW ca. 84 million years ago (Ma). Classic palaeomagnetic data from the Scaglia Rossa limestone of Italy are the primary argument against the existence of ca. 84 Ma TPW. Here we present a new high-resolution palaeomagnetic record from two overlapping stratigraphic sections in Italy that provides evidence for a ~12° TPW oscillation from 86 to 78 Ma. This observation represents the most recent large-scale TPW documented and challenges the notion that the spin axis has been largely stable over the past 100 million years.
Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. The aim of the present study was to characterize the mediators responsible for the FS hypertrophic action ...on skeletal muscle in male mice. Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. First, we tested whether type 1 IGF receptor (IGF-IR) is required for FS-induced hypertrophy. By using mice expressing a dominant-negative IGF-IR in skeletal muscle, we showed that IGF-IR inhibition blunted by 63% fiber hypertrophy caused by FS. Second, we showed that FS caused the same degree of fiber hypertrophy in wild-type and IGF-II knockout mice. We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. We investigated whether Akt phosphorylation is required for the FS action. By cotransfecting a dominant-negative form of Akt together with FS, we showed that Akt inhibition reduced by 65% fiber hypertrophy caused by FS. Second, we evaluated the role of mTOR in FS action. Fiber hypertrophy induced by FS was reduced by 36% in rapamycin-treated mice. Finally, because the activity of S6K is increased by FS, we tested its role in FS action. FS caused the same degree of fiber hypertrophy in wild-type and S6K1/2 knockout mice. In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS.
Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating ...glucocorticoid (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy results from decreased protein synthesis and increased protein degradation. The inhibitory effect of GCs on protein synthesis is thought to result mainly from the inhibition of the p70 ribosomal S6 protein kinase. The stimulatory effect of GCs on muscle proteolysis results from the activation of two major cellular proteolytic systems: ubiquitin proteasome and lysosomal systems. The decrease in muscle production of insulin-like growth factor I (IGF-I), a muscle anabolic growth factor, could contribute to GC-induced muscle atrophy. By activating the phosphatidylinositol-3-kinase/Akt pathway, IGF-I overrides GC action to stunt muscle atrophy. Evidence also indicates that increased production of myostatin, a catabolic growth factor, could play a critical role in GC-induced muscle atrophy.
Recent progress in understanding the role of growth factors in GC-induced muscle atrophy allows investigation into new therapies to minimize this myopathy.
Catabolic states caused by injury are characterized by a loss of skeletal muscle. The anabolic action of IGF-I on muscle and the reduction of its muscle content in response to injury suggest that ...restoration of muscle IGF-I content might prevent skeletal muscle loss caused by injury. We investigated whether local overexpression of IGF-I protein by gene transfer could prevent skeletal muscle atrophy induced by glucocorticoids, a crucial mediator of muscle atrophy in catabolic states. Localized overexpression of IGF-I in tibialis anterior (TA) muscle was performed by injection of IGF-I cDNA followed by electroporation 3 d before starting dexamethasone injections (0.1 mg/kg·d sc). A control plasmid was electroporated in the contralateral TA muscle. Dexamethasone induced atrophy of the TA muscle as illustrated by reduction in muscle mass (403 ± 11 vs. 461 ± 19 mg, P < 0.05) and fiber cross-sectional area (1759 ± 131 vs. 2517 ± 93 μm2, P < 0.05). This muscle atrophy was paralleled by a decrease in the IGF-I muscle content (7.2 ± 0.9 vs. 15.7 ± 1.4 ng/g of muscle, P < 0.001). As the result of IGF-I gene transfer, the IGF-I muscle content increased 2-fold (15.8 ± 1.2 vs. 7.2 ± 0.9 ng/g of muscle, P < 0.001). In addition, the muscle mass (437 ± 8 vs. 403 ± 11 mg, P < 0.01) and the fiber cross-sectional area (2269 ± 129 vs. 1759 ± 131 μm2, P < 0.05) were increased in the TA muscle electroporated with IGF-I DNA, compared with the contralateral muscle electroporated with a control plasmid. Our results show therefore that IGF-I gene transfer by electroporation prevents muscle atrophy in glucocorticoid-treated rats. Our observation supports the important role of decreased muscle IGF-I in the muscle atrophy caused by glucocorticoids.
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