Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels

Luis, A.; Balboa, Elisa; Puebla, Carlos; Vargas, Aníbal A.; Cisterna, Bruno A.; Escamilla, Rosalba; Regueira, Tomás; Sáez, Juan C.

doi:10.1016/j.bbadis.2016.07.003

Cited by 50 publications

(35 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MSTN is known as a negative regulator of muscle mass, determining both muscle fibre number and size in several muscle atrophy models, through the regulation of MuRF‐1 and atrogin‐1 . Dex is well known as an anti‐inflammatory drug, but high doses or long‐term use in rodent models induces muscle atrophy by activating the catabolic pathway . Dex‐induced and CKD‐induced muscle atrophy models also show the negative correlation between the increased level of MSTN and decreased muscle mass .…”

Section: Discussionmentioning

confidence: 99%

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

105

View full text Add to dashboard Cite

Background Skeletal muscle atrophy is defined as a reduction of muscle mass caused by excessive protein degradation. However, the development of therapeutic interventions is still in an early stage. Although glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex‐4) and dulaglutide, are widely used for the treatment of diabetes, their effects on muscle pathology are unknown. In this study, we investigated the therapeutic potential of GLP‐1R agonist for muscle wasting and the mechanisms involved. Methods Mouse C2C12 myotubes were used to evaluate the in vitro effects of Ex‐4 in the presence or absence of dexamethasone (Dex) on the regulation of the expression of muscle atrophic factors and the underlying mechanisms using various pharmacological inhibitors. In addition, we investigated the in vivo therapeutic effect of Ex‐4 in a Dex‐induced mouse muscle atrophy model (20 mg/kg/day i.p.) followed by injection of Ex‐4 (100 ng/day i.p.) for 12 days and chronic kidney disease (CKD)‐induced muscle atrophy model. Furthermore, we evaluated the effect of a long‐acting GLP‐1R agonist by treatment of dulaglutide (1 mg/kg/week s.c.) for 3 weeks, in DBA/2J‐mdx mice, a Duchenne muscular dystrophy model. Results Ex‐4 suppressed the expression of myostatin (MSTN) and muscle atrophic factors such as F‐box only protein 32 (atrogin‐1) and muscle RING‐finger protein‐1 (MuRF‐1) in Dex‐treated C2C12 myotubes. The suppression effect was via protein kinase A and protein kinase B signalling pathways through GLP‐1R. In addition, Ex‐4 treatment inhibited glucocorticoid receptor (GR) translocation by up‐regulating the proteins of GR inhibitory complexes. In a Dex‐induced muscle atrophy model, Ex‐4 ameliorated muscle atrophy by suppressing muscle atrophic factors and enhancing myogenic factors (MyoG and MyoD), leading to increased muscle mass and function. In the CKD muscle atrophy model, Ex‐4 also increased muscle mass, myofiber size, and muscle function. In addition, treatment with a long‐acting GLP‐1R agonist, dulaglutide, recovered muscle mass and function in DBA/2J‐mdx mice. Conclusions GLP‐1R agonists ameliorate muscle wasting by suppressing MSTN and muscle atrophic factors and enhancing myogenic factors through GLP‐1R‐mediated signalling pathways. These novel findings suggest that activating GLP‐1R signalling may be useful for the treatment of atrophy‐related muscular diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

105

View full text Add to dashboard Cite

show abstract

“…This anti-inflammatory effect of LFXY was comparable to DEX, a widely clinical-used anti-inflammatory agent. According to our literature review, high doses and prolonged use of DEX induce side effects, such as reduction in tetanic stimuli-induced force, muscular atrophy, and neurobehavioral problems [51, 52]. Hence, there is an urgent need to develop novel effective medications for prevention and therapies.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Li‐Fei‐Xiao‐Yan Prescription on Lipopolysaccharide‐Induced Acute Lung Injury via Inhibition of Oxidative Stress and the TLR4/NF‐κB Pathway

Gui

et al. 2017

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Li-Fei-Xiao-Yan prescription (LFXY) has been clinically used in China to treat inflammatory and infectious diseases including inflammatory lung diseases. The present study was aimed at evaluating the potential therapeutic effects and potential mechanisms of LFXY in a murine model of lipopolysaccharide- (LPS-) induced acute lung injury (ALI). In this study, the mice were orally pretreated with LFXY or dexamethasone (positive drug) before the intratracheal instillation of LPS. Our data indicated that pretreatment with LFXY enhanced the survival rate of ALI mice, reversed pulmonary edema and permeability, improved LPS-induced lung histopathology impairment, suppressed the excessive inflammatory responses via decreasing the expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and chemokine (MIP-2) and inhibiting inflammatory cells migration, and repressed oxidative stress through the inhibition of MPO and MDA contents and the upregulation of antioxidants (SOD and GSH) activities. Mechanistically, treatment with LFXY significantly prevented LPS-induced TLR4 expression and NF-κB (p65) phosphorylation. Overall, the present study suggests that LFXY protected mice from acute lung injury induced by LPS via inhibition of TLR4/NF-κB p65 activation and upregulation of antioxidative enzymes and it may be a potential preventive and therapeutic agent for ALI in the clinical setting.

show abstract

“…An unexpected and recent finding was that de novo expression of connexin hemichannels explain the glucocorticoid-induced skeletal muscle atrophy [91], a condition frequently observed in patients under chronic treatment with glucocorticoids due to inflammatory conditions. Myofibers deficient in Cx43 and Cx45 expression do not undergo atrophy after chronic treatment with dexamethasone, a synthetic glucocorticoid widely used in long term clinical treatments.…”

Section: Connexins and Pannexins In Skeletal Musclementioning

confidence: 99%

“…One of these mechanisms seems to be the lack of a neuron-derived factor in denervated myofibers [106]. A second mechanism could be the direct induction in connexin expression, as in the case of glucocorticoids known to induce the expression of Cx43 [91], and a third mechanism could involve the role of pro-inflammatory mediators, as described above. And of course, under certain conditions two or all three mechanisms could act in an orchestrated fashion with a more negative outcome for skeletal muscle functions.…”

Section: Connexins and Pannexins In Skeletal Musclementioning

confidence: 99%

Connexins and Pannexins in Bone and Skeletal Muscle

Plotkin

Davis

Cisterna

et al. 2017

Curr Osteoporos Rep

Self Cite

View full text Add to dashboard Cite

Purpose of review To discuss the current knowledge on the role of connexins and pannexins in the musculoskeletal system. Recent findings Connexins and pannexins are crucial for the development and maintenance of both bone and skeletal muscle. In bone, the existence of connexin and more recently pannexin channels in osteoblasts, osteoclasts, and osteocytes has been described, and shown to be essential for normal skeletal development and bone adaptation. In skeletal muscles, connexins and pannexins play important roles during development and regeneration through coordinated regulation of metabolic functions via cell-to-cell communication. Further, under pathological conditions, altered expression of these proteins can promote muscle atrophy and degeneration by stimulating inflammasome activity. Summary In the current review, we highlight the important roles of connexins and pannexins in the development, maintenance, and regeneration of musculoskeletal tissues, with emphasis on the mechanisms by which these molecules mediate chemical (e.g., ATP and PGE2) and physical (e.g. mechanical stimulation) stimuli that target the musculoskeletal system and their involvement in the pathophysiological changes in both genetic and acquired diseases.

show abstract

Dexamethasone-induced muscular atrophy is mediated by functional expression of connexin-based hemichannels

Cited by 50 publications

References 42 publications

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

Protective Effects of Li‐Fei‐Xiao‐Yan Prescription on Lipopolysaccharide‐Induced Acute Lung Injury via Inhibition of Oxidative Stress and the TLR4/NF‐κB Pathway

Connexins and Pannexins in Bone and Skeletal Muscle

Contact Info

Product

Resources

About