Altered Gene Expression in Steroid-Treated Denervated Muscle (original) (raw)
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Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy, 2003
Administration of glucocorticoids results in hypertension, cardiac hypertrophy, and general myopathy. The present study analyzed the acute effect of dexamethasone (0.5 mg/100 g for 3 days) or dexamethasone plus insulin-like growth factor-1 (0.35 mg/100 g for 3 days) on differential gene expression in the gastrocnemius muscle and the left ventricular myocardium of rats. Dexamethasone induced atrophy of gastrocnemius muscle. Cathepsin L, and not ubiquitin, was the earliest mediator of skeletal muscle proteolysis induced by dexamethasone. Insulin-like growth factor-1 reversed gastrocnemius muscle mass, and deleted a part of downregulated genes by dexamethasone. On the other hand, dexamethasone administration did not result in cardiac hypertrophy or hypertension. Only prostaglandin D synthase gene was upregulated by dexamethasone in myocardium, and genes related to extracellular matrix and proteinase inhibitor were downregulated. Molecular alteration for hypertrophy might have initiated...
Running Head: Glucocorticoid mediated muscle gene expression Correspondence to
2015
The transcriptional response of skeletal muscle to chronic corticosteroid exposure was examined over 168 hours and compared to the response profiles observed following a single dose of corticosteroid. Male adrenalectomized Wistar rats were given constant rate infusion of 0.3 mg/kg/h methylprednisolone for up to 7 days via subcutaneously implanted mini-pumps. Four control and 40 drug-treated animals were sacrificed at 10 different time points during infusion. Liver total RNAs were hybridized to 44 individual Affymetrix REA230A gene chips. Previously we described a filtration approach for identifying genes of interest in microarray datasets developed from tissues of rats treated with methylprednisolone following acute dosing. Here, a similar approach involving a series of 3 filters was applied sequentially in order to identify genes of interest. These filters were designed to eliminate probe sets that were not expressed in the tissue, not regulated by the drug, or did not meet defined...
Glucocorticoid excess induces preferential depletion of myosin in denervated skeletal muscle fibers
Muscle & Nerve, 1987
The combined effects of dexamethasone treatment (1 mg/Kg/day) plus denervation (DEX-DEN), were studied at 7, 13, and 28 days by microscopic, biochemical, and physiological techniques in plantaris and soleus muscles of adult rats. The results were compared with corresponding dexamethasone-treated (DEX) and denervated (DEN) muscles and appropriate controls. There was a significantly more marked atrophy of all fiber types in the DEX-DEN plantares at 7 and 13 days than in either DEX or DEN muscles. The degree of atrophy was greatest in type 28 fibers in DEX-DEN plantares. Electron microscopy revealed a severe preferential depletion of thick myofilaments in DEX-DEN plantares and solei but not in DEX or DEN muscles. The thick myofilament depletion in DEX-DEN muscles occurred in addition to a severe overall reduction of myofibrillar caliber. Gel electrophoresis showed a marked preferential decrease of myosin heavy chain in DEX-DEN plantares and solei, but not in either DEX or DEN muscles. Myosin light chains were also markedly reduced in DEX-DEN plantares and solei. In vitro physiological studies showed a marked reduction of the denervation-induced twitch potentiation in DEX-DEN solei. Maximal tetanic tension (20 Hz stimulation) per gram weight of muscle as well as the twitch-tetanus ratio was significantly reduced only in DEX-DEN solei in relation to controls. Myosin depletion in DEX-DEN muscles may be due to a severe preferential inhibition of its synthesis coupled with an accelerated catabolism.
Molecular and cellular defects of skeletal muscle in an animal model of acute quadriplegic myopathy
Muscle & Nerve, 2006
Muscle denervation and concomitant high-dose dexamethasone treatment in rodents produces characteristic pathologic features of severe muscle atrophy and selective myosin heavy filament (MyHC) depletion, identical to those seen in acute quadriplegic myopathy (AQM), also known as critical illness myopathy. We tested the hypothesis that defective pre-translational processes contribute to the atrophy and selective MyHC depletion in this model. We examined the effects of combined glucocorticoid-denervation treatment on MyHC and actin mRNA populations; we also studied mRNA expression of the myogenic regulatory factors (MRFs), primary transcription factors for MyHC. Adult female rats were subjected to proximal sciatic denervation followed by high-dose dexamethasone (DD) treatment (5 mg/kg body weight daily) for 7 days. Disease controls included rats treated with denervation alone (DN) or dexamethasone alone (DX). At 1 week the plantaris atrophied by ϳ42% in DD muscles. DD treatment resulted in selective MyHC protein depletion; actin protein concentration was not significantly changed. Despite an increase in total RNA concentration in DN and DD muscles, MyHC and actin mRNA concentrations were significantly decreased in these muscles. MyHC mRNA showed a significantly more extensive depletion relative to actin mRNA in DD muscles. Glucocorticoid treatment did not influence a denervation-induced increase in the mRNA expression of the MRFs. We conclude that a deleterious interaction between glucocorticoid and denervation treatments in skeletal muscle is responsible for pre-translational defects that reduce actin and MyHC mRNA substrates in a disproportionate fashion. The resultant selective MyHC depletion contributes to the severe muscle atrophy.
The Journal of Physiology, 2013
• Glucocorticoids are stress hormones used in the treatment of many chronic inflammatory diseases including asthma. They exert most of their physiological/pharmacological actions by regulating the activity of genes involved in the inflammatory response. However, they also have rapid/non-genomic effects whose functions are poorly understood. • In this study we used two widely prescribed glucocorticoids, beclomethasone dipropionate and prednisolone acetate, to investigate whether these hormones have rapid/non-genomic effects in mammalian skeletal muscles. • Both glucocorticoids increased maximum force in slow-twitch muscle fibres/cells without significantly affecting that of fast-twitch muscle fibres. • The increase in force occurred within 10 min and was blocked by an inhibitor of the glucocorticoid receptor and a protein (antibody) that binds the receptor. • These findings suggest that these hormones/drugs have rapid/non-genomic effects in mammalian skeletal muscles; these effects are mediated by a membrane glucocorticoid receptor and are physiologically/pharmacologically beneficial, especially in slow muscles.
The Journal of Steroid Biochemistry and Molecular Biology, 2004
The use of chronic glucocorticoid (GC) therapy for the treatment of inflammatory diseases is limited by associated metabolic side effects, including muscle atrophy. Therefore, selective glucocorticoid receptor-(GR)-binding ligands that maintain anti-inflammatory activity and demonstrate diminished side-effect profiles would have great therapeutic utility. In this work, we use Taqman PCR and ELISA methods to show that GCs can inhibit basal, and lipopolysaccharide (LPS)-stimulated levels of cytokines IL-6 and TNF␣, and also the chemokine MCP-1 in a non-inflammatory system such as primary human skeletal muscle cells. In the murine C2C12 skeletal muscle cell line we observe a similar effect of GCs on IL-6 and MCP-1; however, in contrast to previous reports, we observe a time-dependent repression of TNF␣. Furthermore, in skeletal muscle cells, concomitant with cytokine repression, GCs transcriptionally induce glutamine synthetase (GS), a marker for muscle wasting, in an LPS independent manner. Similarly, administration of dexamethasone to mice, previously administered LPS, results in an increase in GS and an inhibition of TNF␣ and MCP-1 in skeletal muscle tissue. Thus, skeletal muscle cells and tissues present a novel system for the identification of selective GR-binding ligands, which simultaneously inhibit cytokine expression in the absence of GS induction.
Quantitative and qualitative adaptations of muscle fibers to glucocorticoids
Muscle & Nerve, 2015
Introduction: The aim of this study was to investigate the effects of shortterm glucocorticoid administration in healthy subjects. Methods: Five healthy men received dexamethasone (8 mg/d) for 7 days. Vastus lateralis muscle biopsy and knee extension torque measurement were performed before and after administration. A large number of individual muscle fibers were dissected from the biopsy samples (preadministration: n=165; post-administration: n=177). Results: Maximal knee extension torque increased after administration (~13%), while both type 1 and type 2A fibers had decreased cross sectional area (type 1: ~11%, type 2A: ~17%), myosin loss (type 1: ~18%, type 2As: ~32%), and loss of specific force (type 1: ~24%, type 2A: ~33%), which was preferential for fast fibers. Discussion: Short-term dexamethasone administration in healthy subjects elicits quantitative and qualitative adaptations of muscle fibers that precede (and may predict) the clinical appearance of myopathy in glucocorticoid-treated subjects.
Current Opinion in Clinical Nutrition and Metabolic Care, 2010
Purpose of review-The purpose of this review is to discuss novel insight into mechanisms of glucocorticoid-regulated muscle wasting, in particular the role of transcription factors and nuclear cofactors. In addition, novel strategies that may become useful in the treatment or prevention of glucocorticoid-induced muscle wasting are reviewed. Recent findings-Studies suggest that glucocorticoid-induced upregulation of the transcription factors FOXO1 and C/EBPβ and downregulation of MyoD and myogenin are involved in glucocorticoid-induced muscle wasting. In addition, glucocorticoid-induced hyperacetylation caused by increased expression of the nuclear cofactor p300 and its histone acetyl transferase activity and decreased expression and activity of histone deacetylases (HDACs) plays an important role in glucocorticoid-induced muscle proteolysis and wasting. Other mechanisms may also be involved in glucocorticoid-induced muscle wasting, including insulin resistance and storeoperated calcium entry. Novel potential strategies to prevent or treat glucocorticoid-induced muscle wasting include the use of small molecule HDAC activators, dissociated glucocorticoid receptor agonists, and 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Summary-An increased understanding of molecular mechanisms regulating glucocorticoidinduced muscle wasting will help develop new strategies to prevent and treat this debilitating condition.
Influence of corticosteroids on myonuclear domain size in the rat diaphragm muscle
Journal of Applied Physiology, 2004
Skeletal muscle fibers are multinucleated. Each myonucleus regulates gene products and protein expression in only a restricted portion of the muscle fiber, the myonuclear domain (MND). In the rat diaphragm muscle (DIAm), corticosteroid (CoS) treatment causes atrophy of fibers containing myosin heavy chain (MHC): MHC2X and/or MHC2B. We hypothesized that DIAm fiber MND size is maintained during CoS-induced atrophy. Adult male rats received methylprednisolone for 11 days at 1 (CoS-Low, n = 8) or 8 mg·kg−1·day−1 (CoS-High, n = 8). Age-matched (CTL-AgeM, n = 8), sham-operated (SHAM-AgeM, n = 8), and weight-matched (CTL-WtM, n = 8) animals served as controls. In single DIAm fibers, cross-sectional area (CSA), MND size, and MHC expression were determined. Fiber CSA and MND size were similar in CTL-AgeM and SHAM-AgeM groups. Only fibers containing MHCslow or MHC2A displayed smaller CSA in CTL-WtM than in CTL-AgeM and SHAM-AgeM groups, and MND size was reduced in all fibers. Thus fibers cont...
The Journal of Steroid Biochemistry and Molecular Biology, 2008
The purpose of this study was to evaluate the effect of dexamethasone on the contractile apparatus and extracellular matrix (ECM) components of slow-twitch (ST) soleus (Sol) and fast-twitch (FT) extensor digitorum longus (EDL) muscle. The specific aim was to assess the development of glucocorticoid-induced myopathy on the level of contractile apparatus and ECM, paying attention to the expression of fibrillar forming collagen types I and III and nonfibrillar type IV collagen expression in extracellular compartment of muscle.