Glucocorticoid-induced Muscle Wasting Research Articles

LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice

Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.

Glucocorticoid-Induced Myopathy: Typology, Pathogenesis, Diagnosis, and Treatment.

Glucocorticoid-induced myopathy is a non-inflammatory toxic myopathy typified by proximal muscle weakness, muscle atrophy, fatigue, and easy fatigability. These vague symptoms coupled with underlying disorders may mask the signs of glucocorticoid-induced myopathy, leading to an underestimation of the disease's impact. This review briefly summarizes the classification, pathogenesis, and treatment options for glucocorticoid-induced muscle wasting. Additionally, we discuss current diagnostic measures in clinical research and routine care used for diagnosing and monitoring glucocorticoid-induced myopathy, which includes gait speed tests, muscle strength tests, hematologic tests, bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), electromyography, quantitative muscle ultrasound, histological examination, and genetic analysis. Continuous monitoring of patients receiving glucocorticoid therapy plays an important role in enabling early detection of glucocorticoid-induced myopathy, allowing physicians to modify treatment plans before significant clinical weakness arises.

Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling

Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling. Our results show that SIRT6 levels are increased during glucocorticoid-induced reduction of myotube size and during skeletal muscle atrophy in mice. Notably, overexpression of SIRT6 spontaneously decreases the size of primary myotubes in a cell-autonomous manner. On the other hand, SIRT6 depletion increases the diameter of myotubes and protects them against glucocorticoid-induced reduction in myotube size, which is associated with enhanced protein synthesis and repression of atrogenes. In line with this, we find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid-induced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor-mediated increase in IGF2 expression. The increased activation, in turn, leads to nuclear exclusion and transcriptional repression of the FoxO transcription factor, a key activator of muscle atrophy. Further, we find that pharmacological inhibition of SIRT6 protects against glucocorticoid-induced muscle wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of SIRT6 in glucocorticoid-induced muscle atrophy.

Suppression of atrogin-1 and MuRF1 prevents dexamethasone-induced atrophy of cultured myotubes

ObjectiveThe mechanistic role of the ubiquitin ligases atrogin-1 and MuRF1 in glucocorticoid-induced muscle wasting is not fully understood. Here, we tested the hypothesis that glucocorticoid-induced muscle atrophy is at least in part linked to atrogin-1 and MuRF1 expression and that the ubiquitin ligases are regulated by compensatory mechanisms. MethodsThe expression of atrogin-1 and MuRF1 was suppressed individually or in combination in cultured L6 myotubes by using siRNA technique. Myotubes were treated with dexamethasone followed by determination of mRNA and protein levels for atrogin-1 and MuRF1, protein synthesis and degradation rates, and myotube morphology. ResultsSuppression of atrogin-1 resulted in increased expression of MuRF1 and vice versa, suggesting that the ubiquitin ligases are regulated by compensatory mechanisms. Simultaneous suppression of atrogin-1 and MuRF1 resulted in myotube hypertrophy, mainly reflecting stimulated protein synthesis, and prevented dexamethasone-induced myotube atrophy, mainly reflecting inhibited protein degradation. ConclusionsThe results provide evidence for a link between upregulated atrogin-1 and MuRF1 expression and glucocorticoid-induced muscle atrophy. The study also suggests that atrogin-1 and MuRF1 levels are regulated by compensatory mechanisms and that inhibition of both ubiquitin ligases may be needed to prevent glucocorticoid-induced muscle proteolysis and atrophy.

β-Hydroxy-β-methylbutyrate (HMB) prevents dexamethasone-induced myotube atrophy

High levels of glucocorticoids result in muscle wasting and weakness. β-hydroxy-β-methylbutyrate (HMB) attenuates the loss of muscle mass in various catabolic conditions but the influence of HMB on glucocorticoid-induced muscle atrophy is not known. We tested the hypothesis that HMB prevents dexamethasone-induced atrophy in cultured myotubes. Treatment of cultured L6 myotubes with dexamethasone resulted in increased protein degradation and expression of atrogin-1 and MuRF1, decreased protein synthesis and reduced myotube size. All of these effects of dexamethasone were attenuated by HMB. Additional experiments provided evidence that the inhibitory effects of HMB on dexamethasone-induced increase in protein degradation and decrease in protein synthesis were regulated by p38/MAPK- and PI3K/Akt-dependent cell signaling, respectively. The present results suggest that glucocorticoid-induced muscle wasting can be prevented by HMB.

Assessing the metabolic effects of prednisolone in healthy volunteers using urine metabolic profiling

BackgroundGlucocorticoids, such as prednisolone, are widely used anti-inflammatory drugs, but therapy is hampered by a broad range of metabolic side effects including skeletal muscle wasting and insulin resistance. Therefore, development of improved synthetic glucocorticoids that display similar efficacy as prednisolone but reduced side effects is an active research area. For efficient development of such new drugs, in vivo biomarkers, which can predict glucocorticoid metabolic side effects in an early stage, are needed. In this study, we aim to provide the first description of the metabolic perturbations induced by acute and therapeutic treatments with prednisolone in humans using urine metabolomics, and to derive potential biomarkers for prednisolone-induced metabolic effects.MethodsA randomized, double blind, placebo-controlled trial consisting of two protocols was conducted in healthy men. In protocol 1, volunteers received placebo (n = 11) or prednisolone (7.5 mg (n = 11), 15 mg (n = 13) or 30 mg (n = 12)) orally once daily for 15 days. In protocol 2, volunteers (n = 6) received placebo at day 0 and 75 mg prednisolone at day 1. We collected 24 h urine and serum samples at baseline (day 0), after a single dose (day 1) and after prolonged treatment (day 15) and obtained mass-spectrometry-based urine and serum metabolic profiles.ResultsAt day 1, high-dose prednisolone treatment increased levels of 13 and 10 proteinogenic amino acids in urine and serum respectively, as well as levels of 3-methylhistidine, providing evidence for an early manifestation of glucocorticoid-induced muscle wasting. Prednisolone treatment also strongly increased urinary carnitine derivatives at day 1 but not at day 15, which might reflect adaptive mechanisms under prolonged treatment. Finally, urinary levels of proteinogenic amino acids at day 1 and of N-methylnicotinamide at day 15 significantly correlated with the homeostatic model assessment of insulin resistance and might represent biomarkers for prednisolone-induced insulin resistance.ConclusionThis study provides evidence that urinary metabolomics represents a noninvasive way of monitoring the effect of glucocorticoids on muscle protein catabolism after a single dose and can derive new biomarkers of glucocorticoid-induced insulin resistance. It might, therefore, help the development of improved synthetic glucocorticoids.Trial RegistrationClinicalTrials.gov NCT00971724

Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism

Resveratrol (3,5,4′-trihydroxystilbene) has been ascribed multiple beneficial biological effects but the influence of resveratrol on glucocorticoid-induced muscle atrophy is not known. We examined the effects of resveratrol on dexamethasone-induced atrogin-1 and MuRF1 expression, FOXO1 acetylation, protein degradation and atrophy in cultured L6 myotubes. In addition, the role of the deacetylase SIRT1 in the effects of resveratrol was determined by transfecting myotubes with SIRT1 siRNA. The catabolic effects of dexamethasone were prevented by resveratrol and the protective effects of resveratrol on dexamethasone-induced atrogin-1 and MuRF1 expression were abolished in myotubes transfected with SIRT1 siRNA. Results suggest that resveratrol can prevent glucocorticoid-induced muscle wasting and that this effect is at least in part SIRT1-dependent.

C/EBPβ regulates dexamethasone‐induced muscle cell atrophy and expression of atrogin‐1 and MuRF1

Muscle wasting in catabolic patients is in part mediated by glucocorticoids and is associated with increased expression and activity of the transcription factor C/EBPβ. It is not known, however, if C/EBPβ is causally linked to glucocorticoid-induced muscle atrophy. We used dexamethasone-treated L6 myoblasts and myotubes to test the role of C/EBPβ in glucocorticoid-induced expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF1, protein degradation, and muscle atrophy by transfecting cells with C/EBPβ siRNA. In myoblasts, silencing C/EBPβ expression with siRNA inhibited dexamethasone-induced increase in protein degradation, atrogin-1 and MuRF1 expression, and muscle cell atrophy. Similar effects of C/EBPβ siRNA were seen in myotubes except that the dexamethasone-induced increase in MuRF1 expression was not affected by C/EBPβ siRNA in myotubes. In additional experiments, overexpressing C/EBPβ did not influence atrogin-1 or MuRF1 expression in myoblasts or myotubes. Taken together, our observations suggest that glucocorticoid-induced muscle wasting is at least in part regulated by C/EBPβ. Increased C/EBPβ expression alone, however, is not sufficient to upregulate atrogin-1 and MuRF1 expression.

Resveratrol Blocks Glucocorticoid‐induced Muscle Wasting in L6 Cultured Myotubes

Muscle proteolysis during sepsis and other catabolic conditions is, at least in part, regulated by glucocorticoids. Dexamethasone-treated myotubes are a commonly used in vitro model of muscle wasting. We reported recently decreased expression and activity of histone deacetylases (HDACs) including Sirtuin (SIRT) 1 are involved in the development of muscle wasting. We tested the hypothesis that treatment with the HDAC/SIRT1 activator resveratrol would prevent glucocorticoid-induced muscle wasting in cultured myotubes. L6 myotubes were treated for 24 h with 1 μM dexamethasone in the absence or presence of resveratrol (100 μM). After treatment for 24 h, myotubes were harvested for determination of atrogin-1 and MuRF1 levels by real-time PCR and Western blot. Myotube cultures were photographed under a phase contrast microscope at 100X magnification for determination of myotube size. Treatment with dexamethasone resulted in increased expression of atrogin-1 and MuRF1, and this was accompanied by a 25–30% reduction of myotube diameter. Resveratrol treatment inhibited the dexamethasone-induced increases in atrogin-1 and MuRF1 expression and reduction in myotube size. Results suggest that resveratrol treatment may prevent glucocorticoid-induced muscle wasting. HDAC/SIRT1 activation may be a novel therapeutic approach in combating muscle wasting conditions. Supported by R01 NR008545 from the NIH.

Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1β in skeletal muscle

Muscle wasting during sepsis is at least in part regulated by glucocorticoids and is associated with increased transcription of genes encoding the ubiquitin ligases atrogin-1 and muscle-specific RING-finger protein-1 (MuRF1). Recent studies suggest that muscle atrophy caused by denervation is associated with reduced expression of the nuclear cofactor peroxisome proliferator-activated receptor-γ coactivator (PGC)-1β and that PGC-1β may be a repressor of the atrogin-1 and MuRF1 genes. The influence of other muscle-wasting conditions on the expression of PGC-1β is not known. We tested the influence of sepsis and glucocorticoids on PGC-1β and examined the potential link between downregulated PGC-1β expression and upregulated atrogin-1 and MuRF1 expression in skeletal muscle. Sepsis in rats and mice and treatment with dexamethasone resulted in downregulated expression of PGC-1β and increased expression of atrogin-1 and MuRF1 in the fast-twitch extensor digitorum longus muscle, with less pronounced changes in the slow-twitch soleus muscle. In additional experiments, adenoviral gene transfer of PGC-1β into cultured C2C12 myotubes resulted in a dose-dependent decrease in atrogin-1 and MuRF1 mRNA levels. Treatment of cultured C2C12 myotubes with dexamethasone or PGC-1β small interfering RNA (siRNA) resulted in downregulated PGC-1β expression and increased protein degradation. Taken together, our results suggest that sepsis- and glucocorticoid-induced muscle wasting may, at least in part, be regulated by decreased expression of the nuclear cofactor PGC-1β.

Corticosteroids and muscle wasting: role of transcription factors, nuclear cofactors, and hyperacetylation

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. Studies suggest that glucocorticoid-induced upregulation of the transcription factors Forkhead box O 1 and CCAAT/enhancer-binding protein beta 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 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 store-operated calcium entry. Novel potential strategies to prevent or treat glucocorticoid-induced muscle wasting include the use of small molecule histone deacetylase activators, dissociated glucocorticoid receptor agonists, and 11beta-hydroxysteroid dehydrogenase type 1 inhibitors. An increased understanding of molecular mechanisms regulating glucocorticoid-induced muscle wasting will help develop new strategies to prevent and treat this debilitating condition.

Dexamethasone inhibits the stimulation of muscle protein synthesis and PHAS-I and p70 S6-kinase phosphorylation.

Glucocorticoids inhibit protein synthesis in muscle. In contrast, insulin and amino acids exert anabolic actions that arise in part from their ability to phosphorylate ribosomal p70 S6-kinase (p70(S6k)) and eukaryotic initiation factor (eIF)4E binding protein (BP)1 (PHAS-I), proteins that regulate translation initiation. Whether glucocorticoids interfere with this action was examined by giving rats either dexamethasone (DEX, 300 microg. kg(-1). day(-1), n = 10) or saline (n = 10) for 5 days. We then measured the phosphorylation of PHAS-I and p70(S6k) in rectus muscle biopsies taken before and at the end of a 180-min infusion of either insulin (10 mU. min(-1). kg(-1) euglycemic insulin clamp, n = 5 for both DEX- and saline-treated groups) or a balanced amino acid mixture (n = 5 for each group also). Protein synthesis was also measured during the infusion period. The results were that DEX-treated rats had higher fasting insulin, slower glucose disposal, less lean body mass, and decreased protein synthetic rates during insulin or amino acid infusion (P < 0.05 each). DEX did not affect basal PHAS-I or p70(S6k) phosphorylation but blocked insulin-stimulated phosphorylation of PHAS-I- and amino acid-stimulated phosphorylation of both PHAS-I and p70(S6k) (P < 0.01, for each). DEX also increased muscle PHAS-I concentration. These effects can, in part, explain glucocorticoid-induced muscle wasting.

Effect of glucocorticoid excess on skeletal muscle and heart protein synthesis in adult and old rats.

This study was carried out to analyse glucocorticoid-induced muscle wasting and subsequent recovery in adult (6-8 months) and old (18-24 months) rats because the increased incidence of various disease states results in hypersecretion of glucocorticoids in ageing. Adult and old rats received dexamethasone in their drinking water for 5 or 6 d and were then allowed to recover for 3 or 7 d. As dexamethasone decreased food intake, all groups were pair-fed to dexamethasone-treated old rats (i.e. the group that had the lowest food intake). At the end of the treatment, adult and old rats showed significant increases in blood glucose and plasma insulin concentrations. This increase disappeared during the recovery period. Protein synthesis of different muscles was assessed in vivo by a flooding dose of [13C]valine injected subcutaneously 50 min before slaughter. Dexamethasone induced a significant decrease in protein synthesis in fast-twitch glycolytic and oxidative glycolytic muscles (gastrocnemius, tibialis anterior, extensor digitorum longus). The treatment affected mostly ribosomal efficiency. Adult dexamethasone-treated rats showed an increase in protein synthesis compared with their pair-fed controls during the recovery period whereas old rats did not. Dexamethasone also significantly decreased protein synthesis in the predominantly oxidative soleus muscle but only in old rats, and increased protein synthesis in the heart of adult but not of old rats. Thus, in skeletal muscle, the catabolic effect of dexamethasone is maintained or amplified during ageing whereas the anabolic effect in heart is depressed. These results are consistent with muscle atrophy occurring with ageing.

Sensitivity and protein turnover response to glucocorticoids are different in skeletal muscle from adult and old rats. Lack of regulation of the ubiquitin-proteasome proteolytic pathway in aging.

We studied glucocorticoid-induced muscle wasting and subsequent recovery in adult (7-mo-old) and old (22-mo-old) rats, since the increased incidence of various disease states may result in glucocorticoids hypersecretion in aging. Adult and old rats received dexamethasone in their drinking water and were then allowed to recover. Muscle wasting occurred more rapidly in old rats and the recovery of muscle mass was impaired, suggesting that glucocorticoids may be involved in the emergence of muscle atrophy with advancing age. According to measurements in incubated epitrochlearis muscles, dexamethasone-induced muscle wasting mainly resulted from increased protein breakdown in the adult, but from depressed protein synthesis in the aged animal. Increased expression of cathepsin D, m-calpain, and ubiquitin was observed in the muscles from both dexamethasone-treated adult and old rats. By contrast, the disappearance of the stimulatory effect of glucocorticoids on protein break-down in aging occurred along with a loss of ability of steroids to enhance the expression of the 14-kD ubiquitin carrier protein E2, which is involved in protein substrates ubiquitinylation, and of subunits of the 20 S proteasome (the proteolytic core of the 26 S proteasome that degrades ubiquitin conjugates). Thus, if glucocorticoids play any role in the progressive muscle atrophy seen in aging, this is unlikely to result from an activation of the ubiquitin-proteasome proteolytic pathway.

Exercise inhibits glucocorticoid-induced glutamine synthetase expression in red skeletal muscles.

One purpose of this study was to determine whether the suppression of glucocorticoid-induced glutamine synthetase (GS) gene expression by exercise is localized to fiber types that are known to be primarily recruited during endurance running. A second purpose examined whether denervation, which is associated with a reduction in contractile activity, would upregulate GS expression. Exercise consisted of treadmill running at 31 m/min for 12-16 wk. Glucocorticoid treatment (100 mg/kg body wt hydrocortisone 21-acetate) was administered during the last 11 days of the exercise program. Basal GS expression was lowest (GS enzyme activity, 43 +/- 3 nmol.h-1.mg protein-1; GS mRNA, 1.0 arbitrary units) in the slow-twitch red soleus, a muscle type that is known to resist glucocorticoid-induced muscle wasting, intermediate (74 +/- 10 and 1.7 +/- 0.2) in fast-twitch red quadriceps, a muscle type susceptible to atrophy, and highest (106 +/- 16 and 5.4 +/- 1.3) in fast-twitch white quadriceps, a muscle type known to be most susceptible to atrophy. Hormone treatment increased GS enzyme activity and mRNA by two- to fourfold in all muscle types. Exercise diminished GS enzyme activity and mRNA in the fast-twitch red fibers to 35-70% of sedentary control values in both basal and glucocorticoid-stimulated muscles. The running also reduced GS enzyme activity in hormone-treated slow-twitch fibers but did not alter basal or glucocorticoid-induced GS expression in fast-twitch white fibers. These results indicate that glucocorticoids induce similar relative GS expression across all muscle types, but the low absolute levels of expression in slow-twitch muscles are not related to any atrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Limited resistance of hypertrophied skeletal muscle to glucocorticoids

Male hypophysectomized rats were initially assigned to a control or an overloaded group that underwent compensatory hypertrophy of plantaris muscles to steady-state levels following removal of synergistic musculature. Plantaris muscle mass of overloaded animals was higher than that of controls by 38% (391 ± 8 vs 284 ± 7 mg) and glucocorticoid cytosol specific binding concentrations, using [ 3H]triamcinolone acetonide (TA) as the labeled steroid, was also significantly higher in hypertrophied muscles (83.3 ± 3.9 fmol · mg protein −1) than in control muscles (56.3 ± 3.9fmol · mg protein −1). Cortisone acetate (CA) was then administered daily subcutaneously in high, 100 mg; intermediate, 10 mg; or low, l.0mg · kg −1 body wt doses. Groups of rats were killed after 1/4, 2 days and 7 days. Absolute muscle mass losses after 7 days of CA treatment were approx 80 mg with high doses and 60 mg with intermediate doses in both hypertrophied and control muscles. The low CA dose did not produce atrophy. The absolute depletion of [ 3H] TA binding activity with CA treatment was always greater in hypertrophied muscles of high and intermediate dose treated than those of their respective controls, but TA binding capacities remained higher in hypertrophied muscles than in controls at almost all time points in all treatment groups. Unlike previous findings in which the simultaneous initiation of overload prevented glucocorticoid induced muscle wasting, no resistance to the effect of CA treatment was observed when treatment was begun after hypertrophy had occurred.

Thigh muscle mass and function in patients treated with glucocorticoids.

Treatment with glucocorticoids causes wasting of proximal skeletal muscles. There is evidence that physical training improves muscle mass and strength in glucocorticoid-treated rats. Whether this is also true in humans is unknown. The present investigation was designed to establish in what respect moderate physical training may alter muscle mass and function as assessed quantitatively by computed tomography (CT) and with an isokinetic dynamometer (Cybex II). Compared with matched controls, both female (n = 17) and male (n = 22) patients treated with prednisone (15.4 +/- 6.6 mg die-1) had a lower mid-thigh muscle area of 20 and 45% and an increased mid-thigh fat/muscle ratio of 25 and 100%, respectively. The mean peak torque and the total work output of the thigh muscle were lower by 20-30% (n = 14). Fifty days of isokinetic training in six patients increased the thigh muscle area, decreased the thigh fat area and normalized the mean peak torque and total work output. Thus, glucocorticoid-induced muscle wasting can be reversed by increasing physical activity.

Evidence that prednisone-induced myopathy is reversed by physical training.

Treatment with glucocorticoids causes wasting of proximal skeletal muscles. There is evidence that physical training improves muscle mass and strength in glucocorticoid-treated rats. Whether this is also true in humans is not known. The present investigation was designed to establish in what respect moderate physical training may alter muscle mass and function as assessed quantitatively by computed tomography (CT) and an isokinetic dynamometer (Cybex II). Compared with matched normal subjects (n = 12), patients (n = 12) treated with prednisone [12.6 +/- 3.3 (+/- SD) mg/day] had a 20% lower midthigh muscle area and a 36% increase in midthigh fat to muscle ratio. The mean peak torque and the total work output of the thigh muscle were lower by more than 20%. Baseline measurements of total work output or peak torque at all tested velocities increased with midthigh muscle area (r = 0.73; n = 24; P less than 0.001). Fifty days of isokinetic training in 12 patients increased the thigh muscle area, decreased the thigh fat area, and normalized the mean peak torque and total work output. The increase in peak torque was inversely correlated with the daily dose of prednisone (r = 0.60; n = 12; P less than 0.05). Thus, glucocorticoid-induced muscle wasting can be reversed by increasing physical activity in patients taking a low to moderate dose of prednisone.

Interaction of glucocorticoids and androgens with skeletal muscle

This review is a discussion of recent developments in our understanding of the metabolic changes that occur in skeletal muscle following treatment with glucocorticoid and androgenic steroid hormones. Exposure of muscle to glucocorticoids results in protein wasting due to a reduction in protein synthesis and an increase in intracellular proteolysis. The protease involved in this response appears to be located in the myofibrillar fraction and its activity is increased by glucocorticoid treatment as well as starvation, diabetes, and tumor-induced cachexia. Treatment with androgens causes an anabolic response in skeletal muscle, mainly due to enhancement of protein-synthesizing machinery. These metabolic changes are reviewed in the light of our current knowledge of the functional role of receptor proteins in steroid hormone action. In rat muscle, two classes of receptors are present that bind cortisol and the synthetic steroids dexamethasone and triamcinolone acetonide, respectively. The cortisol-binding macro-molecule resembles cortisol-binding glubulin or transcortin in several of its physicochemical properties. Attempts to identify specific receptors for androgens in rat skeletal muscle have not been successful. However, in this tissue androgens compete, both in vivo and in vitro, with the receptor proteins that bind dexamethasone. Thus the antagonism of glucocorticoid-induced muscle wasting by concomitant androgen administration may be a consequence of the competition between these steroids for the same site on a receptor in muscle which mediates the catabolic action of glucocorticoids. Current progress in the area of muscle response to steroidal hormones depends on the development of procedures for the measurement and identification of proteolytic enzymes in muscles that are involved in the muscle-wasting diseases. A new approach to the study of muscle protein degradation is based on evidence that 3-methylhistidine is a unique amino acid insofar as it is present in skeletal muscle in relatively high concentrations. The methylation of histidine to form this derivative takes place only after histidine is incorporated into protein. Since the methyl derivative is not reutilized for protein synthesis, the rate of release of 3-methylhistidine from muscle serves as a marker for protein degradation. Future studies are also required to assess the role of normal and abnormal concentrations of blood glucocorticoids in muscle metabolism, and to delineate the sequence of events occurring in these target cells following cytoplasmic binding of the hormones and culminating in the catabolic response.