<i>Cyclic AMP-mediated pleiotropic effects of glucagon-like peptide-1 receptor activation</i>. Focus on “Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a”

Ye, Yumei; Birnbaum, Yochai

doi:10.1152/ajpcell.00419.2012

Cited by 7 publications

(5 citation statements)

References 14 publications

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“…However, it was barely detectible in homozygous Glp1r −/− mice. These data strongly indicate that GLP‐1R is expressed in muscle tissue and C2C12 myotubes, as observed in human muscle satellite cells and cardiomyocytes …”

Section: Discussionsupporting

confidence: 73%

“…These data strongly indicate that GLP-1R is expressed in muscle tissue and C2C12 myotubes, as observed in human muscle satellite cells and cardiomyocytes. 25,45 Silveira et al reported that activated cAMP/PKA signalling in skeletal muscle suppresses the UPS 46 and activated AKT signalling induces protein synthesis in skeletal muscle. [47][48][49] Our data showed that Ex-4 treatment activates both PKA and AKT signalling pathways and inhibits phosphorylated NF-κB protein expression.…”

Section: Discussionmentioning

confidence: 99%

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

Hong

Lee

Jeong

et al. 2019

J cachexia sarcopenia muscle

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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.

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Section: Discussionsupporting

confidence: 73%

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

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“…Final dose selection for GAlbudAb bracketed this target level and contained a one-log concentration range. Dose selection for exendin-4 was based on previous studies [18,33]. …”

Section: Resultsmentioning

confidence: 99%

Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat

Bao

Holt

Prince

et al. 2013

Cardiovasc Diabetol

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Background: Glucagon-like peptide-1 (GLP-1) and its mimetics reduce infarct size in the setting of acute myocardial ischemia/reperfusion (I/R) injury. However, the short serum half-life of GLP-1 and its mimetics may limit their therapeutic use in acute myocardial ischemia. Domain antibodies to serum albumin (AlbudAbs) have been developed to extend the serum half-life of short lived therapeutic proteins, peptides and small molecules. In this study, we compared the effect of a long acting GLP-1 agonist, DPP-IV resistant GLP-1 (7-36, A8G) fused to an AlbudAb (GAlbudAb), with the effect of the GLP-1 mimetic, exendin-4 (short half-life GLP-1 agonist) on infarct size following acute myocardial I/R injury. Methods: Male Sprague-Dawley rats (8-week-old) were treated with vehicle, GAlbudAb or exendin-4. Myocardial ischemia was induced 2 h following the final dose for GAlbudAb and 30 min post the final dose for exendin-4. In a subgroup of animals, the final dose of exendin-4 was administered (1 μg/kg, SC, bid for 2 days) 6 h prior to myocardial ischemia when plasma exendin-4 was at its minimum concentration (C min ). Myocardial infarct size, area at risk and cardiac function were determined 24 h after myocardial I/R injury. Results: GAlbudAb and exendin-4 significantly reduced myocardial infarct size by 28% and 23% respectively, compared to vehicle (both p < 0.01 vs. vehicle) after I/R injury. Moreover, both GAlbudAb and exendin-4 markedly improved post-ischemic cardiac contractile function. Body weight loss and reduced food intake consistent with the activation of GLP-1 receptors was observed in all treatment groups. However, exendin-4 failed to reduce infarct size when administered 6 h prior to myocardial ischemia, suggesting continuous activation of the GLP-1 receptors is needed for cardioprotection. Conclusions: Cardioprotection provided by GAlbudAb, a long acting GLP-1 mimetic, following myocardial I/R injury was comparable in magnitude, but more sustained in duration than that produced by short-acting exendin-4. Very low plasma concentrations of exendin-4 failed to protect the heart from myocardial I/R injury, suggesting that sustained GLP-1 receptor activation plays an important role in providing cardioprotection in the setting of acute myocardial I/R injury. Long-acting GLP-1 agonists such as GAlbudAb may warrant additional evaluation as novel therapeutic agents to reduce myocardial I/R injury during acute coronary syndrome.

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“…Therefore, TGR5 activation may result in cAMP accumulation and/or receptor internalization 5 . cAMP is introduced to stimulate cardiac function 22 , but mice with biliary fibrosis show cardiac dysfunction 6 . The influence of bile acids in heart seems likely due to an integration with TGR5 and muscarinic receptors, the plasma membrane G-protein-coupled receptors, in addition to the nuclear receptors, such as the FXR and PXR xenobiotic receptors 2,3 .…”

Section: Discussionmentioning

confidence: 99%

TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

Cheng

Chang

Kuo

et al. 2019

Sci Rep

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Left ventricular hypertrophy is an independent risk factor in diabetic patients. TGR5 is shown to express in hearts, but its functional role in diabetes-induced cardiac hypertrophy remained unclear. The current study investigated the role of TGR5 on high glucose-induced hypertrophy of H9C2 cells. After incubation with a high level of glucose, H9C2 cells showed hypertrophic responses. Activation of TGR5 by lithocholic acid (LCA) ameliorated cell hypertrophy and enhanced SERCA2a and phosphorylated phospholamban (PLN) expression in H9C2 cells. Triamterene inhibited these effects at an effective dose to block TGR5. However, LCA failed to modify the free radical elevation induced by high-glucose in the H9c2 cells. Moreover, PKA inhibitors, but not an Epac blocker, markedly improved hyperglycemia-induced hypertrophy and attenuated the increased SERCA2a expression by LCA; it also attenuated the phosphorylated PLN and SERCA2a protein expression levels in high glucose-treated H9C2 cells. In conclusion, TGR5 activation stimulated protein kinase A (PKA) to enhance PLN phosphorylation, which activated SERCA2a to remove Ca 2+ from cytosol to sarcoplasmic reticulum in addition to the reduction of calcineurin/NFAT pathway signaling to ameliorate the hyperglycemia-induced cardiac hypertrophy shown in cardiomyocytes. TGR5 may service as a new target in the control of diabetic cardiomyopathy.

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Cyclic AMP-mediated pleiotropic effects of glucagon-like peptide-1 receptor activation. Focus on “Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a”

Cited by 7 publications

References 14 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

Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat

TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells

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