Glucocorticoid-induced skeletal muscle atrophy

Schakman, Olivier; Kalista, Stéphanie; Barbe, Catherine; Loumaye, Audrey; Thissen, Jean‐Paul

doi:10.1016/j.biocel.2013.05.036

Cited by 508 publications

(477 citation statements)

References 129 publications

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“…On the other hand, glucocorticoids did not decrease in either genotype the weight of the slow twitch type I-dominated soleus muscle, a muscle type shown to be less sensitive to the action of the hormones. (46) These changes in bone and muscle mass induced by glucocorticoids occurred in the absence of alterations in total mouse body weight (Fig. 2C).…”

Section: Resultsmentioning

confidence: 82%

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Sato

Cregor

Delgado‐Calle

et al. 2016

Journal of Bone and Mineral Research

105

108

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Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/b-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/b-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost -/-mice. The high bone mass exhibited by Sost -/-mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost -/-mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/b-catenin pathway by decreasing the expression of genes associated with both anticatabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost -/-mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/b-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/b-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/b-catenin signaling.

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Section: Resultsmentioning

confidence: 82%

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Sato

Cregor

Delgado‐Calle

et al. 2016

Journal of Bone and Mineral Research

105

108

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“…Glucocorticoid levels are increased under conditions of physiological stress as well as in many illnesses and are therefore important inducers of muscle wasting (reviewed in Ref. 92). Not surprisingly, glucocorticoids induce the expression of the MuRF1 and atrogin-1 in muscle (12) but do so through multiple mechanisms.…”

Section: Integration Of Signaling Pathways To Modulate Ups Function Imentioning

confidence: 99%

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

Bilodeau

Coyne

Wing

2016

American Journal of Physiology-Cell Physiology

130

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Bilodeau PA, Coyne ES, Wing SS. The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. Am J Physiol Cell Physiol 311: C392-C403, 2016. First published August 10, 2016; doi:10.1152/ajpcell.00125.2016.-Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3␤, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.hormones; muscle atrophy SKELETAL MUSCLE SERVES TWO essential functions, a contractile function for locomotion/maintenance of posture and a metabolic function as the protein reservoir of the body. The myofibers that make up the muscle consist primarily of myofibrillar proteins. The ability of the body to maintain posture or to move arises from the precise organization of myofibrillar proteins into a contractile unit called the sarcomere. The sarcomere consists of thick filaments containing primarily myosin that can slide over thin filaments containing primarily actin. Both types of filaments contain additional regulatory proteins and are linked to the ␣-actinin-containing Z disk, the thin filaments directly so and the thick filaments via titin. Vimentin and desmin are intermediate filaments that serve to anchor sarcomeres properly at the Z disks. These myofibrillar proteins, as well as the sarcoplasmic proteins, also serve as the protein reservoir of the body. Upon fasting, once hepatic glycogen stores are depleted, muscle protein degradation must be activated to provide amino acids to the liver for gluconeogenesis. These amino a...

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“…The type, dose and duration of steroid treatment determine the occurrence and severity of myopathy. Fluorinated steroids (such as dexamethasone or betamethasone) cause myopathy more frequently than non-fluorinated agents (such as prednisolone and hydrocortisone) (211). The reason why fluorinated agents are more frequently associated to myopathy is not clear, but it could be speculated that different GCs exert different genomic and non-genomic actions and impact on different signalling pathways, having different anti-inflammatory or anti-proliferative effects, with consequent different metabolic outcomes (212).…”

Section: Muscle In Csmentioning

confidence: 99%

“…Mechanism " GC-induced muscle atrophy affects mainly fast-twitch or type II fibres with less or no impact observed in type I, the more oxidative type of fibres (211,215). Histological features of GC-related myopathy are nonspecific atrophy of type IIb muscle fibres, the absence of inflammatory infiltrate, variations in fibre size with centrally placed nuclei and, rarely, signs of muscle necrosis (215).…”

Section: Muscle In Csmentioning

confidence: 99%

Metabolic comorbidities in Cushing's syndrome

Ferraú

Korbonits

2015

European Journal of Endocrinology

145

121

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Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

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Glucocorticoid-induced skeletal muscle atrophy

Cited by 508 publications

References 129 publications

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

Metabolic comorbidities in Cushing's syndrome

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