Neuregulin-1β attenuates sepsis-induced diaphragm atrophy by activating the PI3K/Akt signaling pathway

Wu, Jin; Liu, Hua; Chu, Ting; Peng, Jiang; Li, Shitong

doi:10.1007/s10974-019-09512-2

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…At present, a large amount of research has shown that skeletal muscle protein degradation pathways mainly include caspase, calpain, ubiquitin-proteasome system (UPS), and autophagylysosome (AL) pathway, among which, UPS and AL play the most important role (6,7). Therein, the role of UPS in septic diaphragm atrophy has been demonstrated in our previous study (8). However, the role of autophagy in sepsis-induced muscle atrophy is still not clear (9).…”

Section: Introductionmentioning

confidence: 89%

Neuregulin-1β Alleviates Sepsis-Induced Skeletal Muscle Atrophy by Inhibiting Autophagy via AKT/mTOR Signaling Pathway in Rats

Yin

Lin

Xie

et al. 2021

Shock

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Background: Several studies have shown that excessive protein degradation is a major cause of skeletal muscle atrophy induced by sepsis, and autophagy is the main pathway participating in protein degradation. However, the role of autophagy in sepsis is still controversial. Previously, we found that neuregulin-1b (NRG-1b) alleviated sepsis-induced diaphragm atrophy through the phosphatidylinositol-3 kinase signaling pathway. Akt/mechanistic target of rapamycin (mTOR) is a classic signaling pathway to regulate autophagy, which maintains intracellular homeostasis. This study aimed to investigate whether NRG-1b could alleviate sepsis-induced skeletal muscle atrophy by regulating autophagy. Methods: L6 rat myoblast cells were differentiated using 2% fetal bovine serum into myotubes, which were divided into four groups: Con group treated with normal serum; Sep group treated with septic serum to form a sepsis cell model; septic serum þ NRG-1b (SN) group treated with septic serum for 24 h followed by injection with NRG-1b and incubation for another 48 h; and serumþNRG-1bþLY294002 group, in which the PI3K inhibitor LY294002 was added 30 min before NRG-1b, and other treatments were similar to those in SN group. Effects of NRG-1b were also evaluated in vivo using Sprague-Dawley (SD) rats, in which sepsis was induced by cecal ligation and puncture (CLP). Results: In L6 myotubes treated with septic serum, the expression of autophagy-related proteins UNC-51 like kinase 1, p-Beclin-1, and Beclin-1, and the ratio of LC3B II/ I were highly increased, while protein p62 expression was decreased, indicating that autophagy was excessively activated. Moreover, NRG-1 expression was decreased, as detected by confocal immunofluorescence and western blotting. Upon exogenous addition of NRG-1b, autophagy was inhibited by the activation of Akt/mTOR signaling pathway, and cell viability was also increased. These effects disappeared in the presence of LY294002. In SD rats, sepsis was induced by CLP. NRG-1b was shown to inhibit autophagy in these rats via the Akt/mTOR pathway, leading to increased body weight of the septic SD rats and alleviation of atrophy of the tibialis anterior muscle. Conclusion: NRG-1b could alleviate sepsis-induced skeletal muscle atrophy by inhibiting autophagy via the AKT/mTOR signaling pathway.

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Section: Introductionmentioning

confidence: 89%

Neuregulin-1β Alleviates Sepsis-Induced Skeletal Muscle Atrophy by Inhibiting Autophagy via AKT/mTOR Signaling Pathway in Rats

Yin

Lin

Xie

et al. 2021

Shock

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“…When that level was >16.7 mmol/L, T2DM was considered established ( Kleinert et al, 2018 ; Yang et al, 2020 ). DM + NRG-1β group and DM group received 30 μg/kg NRG-1β ( via intraperitoneal injection) or the same volume of PBS weekly for 4 weeks, respectively ( Ennequin et al, 2015 ; Wu et al, 2019 ; Liu et al, 2020 ). After a week final treatment of NRG-1β, mice were anesthetized with 1% (w/v) pentobarbital sodium and euthanized by decapitation.…”

Section: Methodsmentioning

confidence: 99%

Neuregulin-1β increases glucose uptake and promotes GLUT4 translocation in palmitate-treated C2C12 myotubes by activating PI3K/AKT signaling pathway

Wu²,

Gong³

et al. 2023

Front. Pharmacol.

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Insulin resistance (IR) is a feature of type 2 diabetes (T2DM) accompanied by reduced glucose uptake and glucose transporter 4 (GLUT4) translocation by skeletal muscle. Neuregulin-1β (NRG-1β) is essential for myogenesis and the regulation of skeletal muscle metabolism. Neuregulin-1β increases insulin sensitivity, promotes glucose uptake and glucose translocation in normal skeletal muscle. Here, we explored whether Neuregulin-1β increased glucose uptake and GLUT4 translocation in palmitate (PA)-treated C2C12 myotubes. After C2C12 myoblasts differentiated into myotubes, we used palmitate to induce cellular insulin resistance. Cells were incubated with or without Neuregulin-1β and glucose uptake was determined using the 2-NBDG assay. The expression level of glucose transporter 4 (GLUT4) was measured via immunofluorescence and Western blotting. MK2206, an inhibitor of AKT, was employed to reveal the important role played by AKT signaling in PA-treated C2C12 myotubes. We then established an animal model with T2DM and evaluated the effects of Neuregulin-1β on body weight and the blood glucose level. The GLUT4 level in the gastrocnemius of T2DM mice was also measured. NRG-1β not only increased glucose uptake by PA-treated myotubes but also promoted GLUT4 translocation to the plasma membrane. The effect of NRG-1β on PA-treated C2C12 myotubes was associated with AKT activation. In T2DM mice, Neuregulin-1β not only improved diabetes-induced weight loss and diabetes-induced hyperglycemia, but also promoted GLUT4 translocation in the gastrocnemius. In summary, Neuregulin-1β increased glucose uptake and promoted translocation of GLUT4 to the plasma membrane in PA-treated C2C12 myotubes by activating the PI3K/AKT signaling pathway.

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“…L6 rat skeletal muscle cells were purchased from Shanghai Institutes for Biological Science (Shanghai, China) and regularly cultured and differentiated according to our previous study [ 32 ]. Thirty minutes before LPS (Sigma-Aldrich) treatment, cells were treated with PBS (control group (C group) and LPS group (L group)), NRG-1 β (10 nM, PeproTech, PBS+NRG group (CN group) and LPS+NRG group (LN group)), or NRG-1 β plus the Akt inhibitor MK-2206 (10 μ M, Selleck, LPS+NRG+MK-2206 group (LNM group)) [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

“…Thirty minutes before LPS (Sigma-Aldrich) treatment, cells were treated with PBS (control group (C group) and LPS group (L group)), NRG-1 β (10 nM, PeproTech, PBS+NRG group (CN group) and LPS+NRG group (LN group)), or NRG-1 β plus the Akt inhibitor MK-2206 (10 μ M, Selleck, LPS+NRG+MK-2206 group (LNM group)) [ 33 ]. Then, except C and CN groups, cells of other groups were treated with LPS (1 μ g/ml) [ 32 ] for 24 h. At the end of incubation, cells were collected for quantifying intracellular ROS with a Reactive Oxygen Species Assay Kit (S0033, Beyotime, China) according to the manufacturer's instructions. Briefly, cells were resuspended with a serum-free medium containing the fluorescent probe DCFH-DA (10 μ M).…”

Section: Methodsmentioning

confidence: 99%

Neuregulin-1β Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway

Liu

Weng

Yao

et al. 2020

Oxidative Medicine and Cellular Longevity

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Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1β (NRG-1β) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1β therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1β application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1β treatment. In vitro, the effects of NRG-1β on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1β inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1β. And NRG-1β activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1β, while MK-2206 blocked these effects of NRG-1β. In conclusion, our findings underlined that NRG-1β could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling.

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Neuregulin-1β attenuates sepsis-induced diaphragm atrophy by activating the PI3K/Akt signaling pathway

Cited by 11 publications

References 38 publications

Neuregulin-1β Alleviates Sepsis-Induced Skeletal Muscle Atrophy by Inhibiting Autophagy via AKT/mTOR Signaling Pathway in Rats

Neuregulin-1β Alleviates Sepsis-Induced Skeletal Muscle Atrophy by Inhibiting Autophagy via AKT/mTOR Signaling Pathway in Rats

Neuregulin-1β increases glucose uptake and promotes GLUT4 translocation in palmitate-treated C2C12 myotubes by activating PI3K/AKT signaling pathway

Neuregulin-1β Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway

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