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

Abstract

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.

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

“…As reported, β2-agonist formoterol was reported to decrease protein degradation partially through inhibiting PI3K-AKT-mTOR mediated ALS, which prevented the muscle mass loss in fasted mice (118). Apart from that, the activation of PI3K-AKT signaling pathway prevented muscle atrophy via mTOR-mediated inhibition of ALS (119,120). Wang et al found that ghrelin ameliorated DOX-induced CMA by inhibiting excess autophagy via stimulating mTOR (62).…”

Single‐cell RNA sequencing reveals the heterogeneity of epithelial cell and fibroblast cells from non‐ to metastatic lymph node OTSCC

“…In previous studies, it has been demonstrated that GAS6/AXT and NRG signaling pathways play significant roles in modulating cellular behavior, such as tumor cell proliferation, tumor development, metastasis, and immunological infiltration. [53][54][55] In addition, it is seen that the communication between epithelial cells through cell-cell interactions is more pronounced in the cluster of NKAIN2 + EPI cells in the context of lymph node metastasis in OTSCC. This is evident in both the incoming and outgoing communication patterns.…”

Nutrition and autophagy deficiency in critical illness

“…The importance of muscle autophagy in critical illness has also been underscored. Although autophagy may contribute to critical illness induced muscle atrophy [44][45][46], its activation overall protects muscle function. In mice with hind-limb ischemia, autophagy inhibition indeed had a dual effect, diminishing muscle peak force while decreasing fibrosis and myofiber size [46].…”