Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling

Son, Young Hoon; Lee, Seok Jin; Lee, Ki Baek; Lee, Jin Haeng; Jeong, Eui Man; Chung, Sun Gun; Park, Sang Chul; Kim, Ingyu

doi:10.1530/joe-14-0490

Cited by 28 publications

(20 citation statements)

References 37 publications

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“…As a generally applied model of skeletal muscle atrophy in vitro , the C2C12 murine myoblasts and primary HSMPCs were induced to differentiate into myotubes. The myotube atrophy and protein degradation were induced by Dexa . As shown in Figure A and B, ALN (0.1–1 μM) dose‐dependently promoted the enlargement in diameters of myotubes, which were over 20 and 40 μm of myotubes differentiated from C2C12 myoblast and HSMPCs, respectively.…”

Section: Resultsmentioning

confidence: 84%

“…The myotube atrophy and protein degradation were induced by Dexa. [29][30][31] As shown in Figure 1A Alendronate prevents Dexa-induced atrophy in C2C12-derived and human skeletal muscle-derived progenitor cell-derived myotubes via SIRT3 mediation Muscle atrophy in vitro is ordinarily determined by both the reduction of myotube diameters and the induction of ubiquitin ligase muscle atrophy F-box or Atrogin-1 expressions, which drive skeletal muscle specific protein degradation. 32 As shown in Figure 3A, myotubes were treated with 1 μM Dexa in the presence or absence of 0.1-1 μM ALN for 24 h. Dexamethasone significantly elevated the Atrogin-1 protein expressions in both C2C12-derived [ Figure 3A(a)] and HSMPC-derived [ Figure 3A(b)] myotubes, which could be significantly reversed by the treatment of ALN in a dosedependent manner.…”

Section: Resultsmentioning

confidence: 99%

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Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin‐3 down‐regulation

Chiu

Yang

et al. 2018

J cachexia sarcopenia muscle

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Background A global consensus on the loss of skeletal muscle mass and function in humans refers as sarcopenia and cachexia including diabetes, obesity, renal failure, and osteoporosis. Despite a current improvement of sarcopenia or cachexia with exercise training and supportive therapies, alternative and specific managements are needed to discover for whom are unable or unwilling to embark on these treatments. Alendronate is a widely used drug for osteoporosis in the elderly and postmenopausal women. Osteopenic menopausal women with 6 months of alendronate therapy have been observed to improve not only lumbar bone mineral density but also handgrip strength. However, the effect and mechanism of alendronate on muscle strength still remain unclear. Here, we investigated the therapeutic potential and the molecular mechanism of alendronate on the loss of muscle mass and strength in vitro and in vivo. Methods Mouse myoblasts and primary human skeletal muscle-derived progenitor cells were used to assess the effects of low-dose alendronate (0.1-1 μM) combined with or without dexamethasone on myotube hypertrophy and myogenic differentiation. Moreover, we also evaluated the effects of low-dose alendronate (0.5 and 1 mg/kg) by oral administration on the limb muscle function and morphology of mice with denervation-induced muscle atrophy and glycerol-induced muscle injury. Results Alendronate inhibited dexamethasone-induced myotube atrophy and myogenic differentiation inhibition in mouse myoblasts and primary human skeletal muscle-derived progenitor cells. Alendronate significantly abrogated dexamethasone-up-regulated sirtuin-3 (SIRT3), but not SIRT1, protein expression in myotubes. Both SIRT3 inhibitor AKG7 and SIRT3-siRNA transfection could also reverse dexamethasone-up-regulated atrogin-1 and SIRT3 protein expressions. Animal studies showed that low-dose alendronate by oral administration ameliorated the muscular malfunction in mouse models of denervation-induced muscle atrophy and glycerol-induced muscle injury with a negative regulation of SIRT3 expression. Conclusions The putative mechanism by which muscle atrophy was improved with alendronate might be through the SIRT3 down-regulation. These findings suggest that alendronate can be a promising therapeutic strategy for management of muscle wasting-related diseases and sarcopenia.

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Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin‐3 down‐regulation

Chiu

Yang

et al. 2018

J cachexia sarcopenia muscle

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show abstract

“…A general principle for myoblast differentiation is contact inhibition and serum deprivation 18, followed by division, elongation, and fusion. Many studies have treated differentiated myotubes with DEX and showed atrophic effects 9, 11, 19. The molecular pathways involved in the atrophic process include the ubiquitin-proteasome system, the lysosomal system, and the calcium-dependent system 20.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Treatment at the Myoblast Stage Enhanced C2C12 Myocyte Differentiation

Han¹,

Yang²,

Kao³

2017

Int. J. Med. Sci.

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Background: Glucocorticoids induce skeletal muscle atrophy in many clinical situations; however, their hypertrophic and pro-differentiation effects on myotubes have rarely been reported. We hypothesized that dexamethasone (DEX) has a dual effect on muscle differentiation, and aimed to develop a new differentiation protocol for C2C12 cell line.Methods: Dose- and time-dependent effect of DEX on C2C12 myoblast cell line was analyzed at myoblast and myotube stage, respectively. The level of differentiation was determined by myh1, pax7, atrogin-1, and myostatin mRNA expression and fusion index.Results: After differentiation and at the myotube stage, DEX treatment has an atrophic effect. Specifically, the myotube was thinner, the expression of atrogin-1 increased, and the protein content of myosin heavy chain decreased. In contrast, when DEX treatment was performed before the onset of differentiation, we observed an increase in myotube diameter and myosin heavy chain levels, and a decrease in the expression of atrogin-1. The ratio of multinuclear myotube cells increased in the DEX treatment group. The optimal treatment concentration and time was 100 μM and 48 h, respectively. Co-treatment with 10 μM DEX and 100 nM insulin further enhanced the process of myotube differentiation.Discussion: This novel finding contributed to the explanation on the stage-specific mechanism of glucocorticoid-induced myopathy. A new formula for myoblast differentiation, containing both DEX and insulin, is proposed. Further research is required to understand the complete mechanism of DEX-induced muscle hypertrophy.

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“…GC response elements have been identified in the promoter of the CAV1 gene, and dexamethasone treatment reduced CAV1 protein and mRNA expression with a concomitant reduction in insulin receptor alpha (IRa) and IRS1 levels in C2C12 myotubes. In addition, CAV1 knockdown decreased the protein levels of IRa and IRS1, and overexpression of CAV1 prevented the dexamethasone-induced decrease in IRa and IRS1 proteins (217). GCs promote proteolytic degradation of myofibrillar and extracellular matrix proteins by inducing the expression of components of the ubiquitin and proteasome system; activating the lysosomal system, as suggested by the presence of markers of autophagy in the muscle of GC-treated animals, and stimulating the calcium-mediated proteolytic system (218).…”

Section: Muscle In Csmentioning

confidence: 92%

Metabolic comorbidities in Cushing's syndrome

Ferraú

Korbonits

2015

European Journal of Endocrinology

149

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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Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling

Cited by 28 publications

References 37 publications

Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin‐3 down‐regulation

Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin‐3 down‐regulation

Dexamethasone Treatment at the Myoblast Stage Enhanced C2C12 Myocyte Differentiation

Metabolic comorbidities in Cushing's syndrome

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