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

Abstract

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-1β (NRG-1β) 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-1β could alleviate sepsis-induced skeletal muscle atrophy by regulating autophagy. 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 + NRG-1β (SN) group treated with septic serum for 24 h followed by injection with NRG-1β and incubation for another 48 h; and serum+NRG-1β+LY294002 group, in which the PI3K inhibitor LY294002 was added 30 min before NRG-1β, and other treatments were similar to those in SN group. Effects of NRG-1β were also evaluated in vivo using Sprague-Dawley (SD) rats, in which sepsis was induced by cecal ligation and puncture (CLP). 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-1β, 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-1β 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. NRG-1β could alleviate sepsis-induced skeletal muscle atrophy by inhibiting autophagy via the AKT/mTOR signaling pathway.