Neuregulin-1β attenuates sepsis-induced diaphragm atrophy by activating the PI3K/Akt signaling pathway
The aim of this study was to investigate the protective effects of neuregulin-1β (NRG-1β) on sepsis-induced diaphragm atrophy and the possible underlying mechanisms. Sprague–Dawley rats were randomly divided into sham, sepsis and NRG groups. Sepsis was induced by cecal ligation and puncture (CLP). In the NRG group, rats received tail vein injections of NRG-1β (10 μg/kg) every 12 h for 72 h after CLP. At 3 days after surgery, diaphragm contractile forces were measured by determining the force-frequency curve and muscle fiber areas by hematoxylin–eosin staining. Moreover, the NRG-1 expression level in the diaphragm was detected by Western blotting. Furthermore, the proteins in the PI3K/Akt signaling pathway and its downstream Akt-mTOR and Akt-FOXO axes were detected by Western blotting analysis. In L6 myotubes treated with lipopolysaccharide (LPS) and NRG-1β, PI3K/Akt signaling pathway-related protein expression was further determined using the PI3K inhibitor LY294002. Exogenous NRG-1β could compensate for sepsis-induced diminished NRG-1 in the diaphragm and attenuate the reduction in diaphragm contractile forces and muscle fiber areas during sepsis. Moreover, NRG-1β treatment could activate the PI3K/Akt signaling pathway in the diaphragm during sepsis. The inhibition of p70S6K and 4E-BP1 on the Akt-mTOR axis and the increased expression of Murf1 on the Akt-FOXO axis were reversed after NRG-1 treatment. In addition, NRG-1β could activate the PI3K/Akt signaling pathway in L6 myotubes treated with LPS, while the PI3K inhibitor LY294002 blocked the effects of NRG-1β. NRG-1 expression in the diaphragm was reduced during sepsis, and exogenously administered recombinant human NRG-1β could attenuate sepsis-induced diaphragm atrophy by activating the PI3K/Akt signaling pathway.
KeywordsSepsis Neuregulin-1 PI3K/Akt pathway Diaphragm Atrophy
This study was supported by the Introduction Program of High-Level Innovation and Entrepreneurship Talents in Jiangsu Province (2018) and the Scientific Research Foundation of Affiliated Hospital of Jiangsu University (jdfyRC2017008).
Compliance with ethical standards
Conflicts of interest
Jin Wu, Hua Liu, Ting Chu, Peng Jiang and Shi-tong Li declare that they have no conflict of interest.
- An T, Zhang Y, Huang Y, Zhang R, Yin S, Guo X, Wang Y, Zou C, Wei B, Lv R, Zhou Q, Zhang J (2013) Neuregulin-1 protects against doxorubicin-induced apoptosis in cardiomyocytes through an Akt-dependent pathway. Physiol Res 62:379–385Google Scholar
- Crossland H, Constantin-Teodosiu D, Gardiner SM, Constantin D, Greenhaff PL (2008) A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle. J Physiol 586:5589–5600. https://doi.org/10.1113/jphysiol.2008.160150 CrossRefGoogle Scholar
- Fang SJ, Wu XS, Han ZH, Zhang XX, Wang CM, Li XY, Lu LQ, Zhang JL (2010) Neuregulin-1 preconditioning protects the heart against ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Chin Med J (Engl) 123:3597–3604. https://doi.org/10.3760/cma.j.issn.0366-6999.2010.24.018 Google Scholar
- Jung B, Nougaret S, Conseil M, Coisel Y, Futier E, Chanques G, Molinari N, Lacampagne A, Matecki S, Jaber S (2014) Sepsis is associated with a preferential diaphragmatic atrophy: a critically ill patient study using tridimensional computed tomography. Anesthesiology 120:1182–1191. https://doi.org/10.1097/ALN.0000000000000201 CrossRefGoogle Scholar
- Kim JA, Park HS, Park KI, Hong GE, Nagappan A, Zhang J, Han DY, Shin SC, Won CG, Kim EH, Kim GS (2013) Proteome analysis of the anti-inflammatory response of flavonoids isolated from Korean Citrus aurantium L. in lipopolysaccharide-induced L6 rat skeletal muscle cells. Am J Chin Med 41:901–912. https://doi.org/10.1142/s0192415x13500602 CrossRefGoogle Scholar
- Maes K, Stamiris A, Thomas D, Cielen N, Smuder A, Powers SK, Leite FS, Hermans G, Decramer M, Hussain SN, Gayan-Ramirez G (2014) Effects of controlled mechanical ventilation on sepsis-induced diaphragm dysfunction in rats. Crit Care Med 42:e772–e782. https://doi.org/10.1097/CCM.0000000000000685 CrossRefGoogle Scholar
- Seethala RR, Hou PC, Aisiku IP, Frendl G, Park PK, Mikkelsen ME, Chang SY, Gajic O, Sevransky J (2017) Early risk factors and the role of fluid administration in developing acute respiratory distress syndrome in septic patients. Ann Intensive Care 7:11. https://doi.org/10.1186/s13613-017-0233-1 CrossRefGoogle Scholar
- Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810. https://doi.org/10.1001/jama.2016.0287 CrossRefGoogle Scholar
- Svanberg E, Frost RA, Lang CH, Isgaard J, Jefferson LS, Kimball SR, Vary TC (2000) IGF-I/IGFBP-3 binary complex modulates sepsis-induced inhibition of protein synthesis in skeletal muscle. Am J Physiol Endocrinol Metab 279:E1145–E1158. https://doi.org/10.1152/ajpendo.2000.279.5.E1145 CrossRefGoogle Scholar
- Wang MM, Hao LY, Guo F, Zhong B, Zhong XM, Yuan J, Hao YF, Zhao S, Sun XF, Lei M, Jiao GY (2017) Decreased intracellular [Ca2+] coincides with reduced expression of Dhprα1s, RyR1, and diaphragmatic dysfunction in a rat model of sepsis. Muscle Nerve 56:1128–1136. https://doi.org/10.1002/mus.25554 CrossRefGoogle Scholar