Estrogen Maintains Skeletal Muscle in Septic Rats Associated with Altering Hypothalamic Inflammation and Neuropeptides

Abstract

Muscle wasting is one of the main contributors to the worse outcomes in sepsis. Whether estrogen could alleviate muscle wasting induced by sepsis remains unclear. This study was designed to test the effect of estrogen on muscle wasting and its relationship with central alteration in sepsis. Thirty Sprague-Dawley rats were divided into 3 groups: control group, sepsis group, and estrogen treated sepsis group. Animals were intraperitoneally injected with lipopolysaccharide (10 mg/kg) or saline, followed by subcutaneous injection of 17β-estradiol (1 mg/kg) or saline. Twenty-four hours later, all animals were killed and their hypothalamus and skeletal muscles were harvested for analysis. Muscle wasting markers, hypothalamic neuropeptides, and hypothalamic inflammatory markers were measured. As a result, lipopolysaccharide administration caused a significant increase in muscle wasting, hypothalamic inflammation, and anorexigenic neuropeptides (POMC and CART) gene expression, and a significant decrease in orexigenic neuropeptides (AgRP and NPY) gene expression. Administration of estrogen signifcantl attenuated lipopolysaccharide-induced muscle wasting (body weight and extensor digitorum longus loss [52 and 62 %], tyrosine and 3-methylhistidine release [17 and 22 %], muscle ring fnger 1 [MuRF-1; 65 %], and muscle atrophy F-box [MAFbx] gene expression), hypothalamic inflammation (Tumor necrosis factor-α and interlukin-1β [69 and 70%]) as well as alteration of POMC, CART and AgRP (61, 37, and 1008 %) expression.In conclusion, estrogen could alleviate sepsis-induced muscle wasting and it was associated with reducing hypothalamic inflammation and alteration of hypothalamic neuropeptides.

Key words

estrogen - muscle wasting - sepsis - hypothalamic neuropeptides - central inflammation

^* Equal contributors.

• References

• 1 Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41: 580-637
• 2 Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 2013; 41: 1167-1174
• 3 Englert JA, Rogers AJ. Metabolism, metabolomics, and nutritional support of patients with sepsis. Clin Chest Med 2016; 37: 321-331
• 4 Weijs PJ, Looijaard WG, Dekker IM, Stapel SN, Girbes AR, Oudemans-van Straaten HM, Beishuizen A. Low skeletal muscle area is a risk factor for mortality in mechanically ventilated critically ill patients. Crit Care (London, England) 2014; 18: R12
• 5 Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, Morris A, Dong N, Rock P. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012; 307: 795-803
• 6 Rice TW, Mogan S, Hays MA, Bernard GR, Jensen GL, Wheeler AP. Randomized trial of initial trophic vs. full-energy enteral nutrition in mechanically ventilated patients with acute respiratory failure. Crit Care Med 2011; 39: 967-974
• 7 Bear DE, Puthucheary ZA, Hart N. Early feeding during critical illness. Lancet Resp Med 2014; 2: 15-17
• 8 Casaer MP, Van den Berghe G. Nutrition in the acute phase of critical illness. N Eng J Med 2014; 370: 1227-1236
• 9 Braun TP, Zhu X, Szumowski M, Scott GD, Grossberg AJ, Levasseur PR, Graham K, Khan S, Damaraju S, Colmers WF, Baracos VE, Marks DL. Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med 2011; 208: 2449-2463
• 10 Wisse BE, Ogimoto K, Tang J, Harris Jr. MK, Raines EW, Schwartz MW. Evidence that lipopolysaccharide-induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology 2007; 148: 5230-5237
• 11 Duan K, Yu W, Lin Z, Tan S, Bai X, Gao T, Xi F, Li N. Endotoxemia-induced muscle wasting is associated with the change of hypothalamic neuropeptides in rats. Neuropeptides 2014; 48: 379-386
• 12 Duan K, Yu W, Lin Z, Tan S, Bai X, Gao T, Xi F, Li N. Insulin ameliorating endotoxaemia-induced muscle wasting is associated with the alteration of hypothalamic neuropeptides and inflammation in rats. Clin Endocrinol 2015; 82: 695-703
• 13 Schroder J, Kahlke V, Staubach KH, Zabel P, Stuber F. Gender differences in human sepsis. Archives of surgery (Chicago, ILL: 1960) 1998; 133: 1200-1205
• 14 Adrie C, Azoulay E, Francais A, Clec’h C, Darques L, Schwebel C, Nakache D, Jamali S, Goldgran-Toledano D, Garrouste-Orgeas M, Timsit JF. Influence of gender on the outcome of severe sepsis: a reappraisal. Chest 2007; 132: 1786-1793
• 15 Rettberg JR, Yao J, Brinton RD. Estrogen: A master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol 2014; 35: 8-30
• 16 Christaki E, Opal Steven M, Keith Jr, James C, Kessinian N, Palardy John E, Parejo Nicolas A, Lavallie E, Racie L, Mounts W, Malamas Michael S, Mewshaw Richard E, Harris Heather A, Vlasuk George P. Estrogen receptor b agonism increases survival in experimentally induced sepsis and ameliorates the genomic sepsis signature: A pharmacogenomic study. J Infect Dis 2010; 201: 1250-1257
• 17 Liu CJ, Lo JF, Kuo CH, Chu CH, Chen LM, Tsai FJ, Tsai CH, Tzang BS, Kuo WW, Huang CY. Akt mediates 17beta-estradiol and/or estrogen receptor-alpha inhibition of LPS-induced tumor necresis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NFkappaB pathway. J Cell Mol Med 2009; 13: 3655-3667
• 18 Nweze IC, Smith JW, Zhang B, Klinge CM, Lakshmanan J, Harbrecht BG. 17beta-Estradiol attenuates cytokine-induced nitric oxide production in rat hepatocyte. J Trauma Acute Care Surg 2012; 73: 408-412
• 19 Cristofaro PA, Opal SM, Palardy JE, Parejo NA, Jhung J, Keith Jr. JC, Harris HA. WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock. Crit Care Med 2006; 34: 2188-2193
• 20 Choudhry MA, Schwacha MG, Hubbard WJ, Kerby JD, Rue LW, Bland KI, Chaudry IH. Gender differences in acute response to trauma-hemorrhage. Shock 2005; 24 (Suppl. 01) 101-106
• 21 Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ, Clegg DJ, Kaplitt MG, Ogawa S. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci USA 2007; 104: 2501-2506
• 22 Abdelfattah KR, Gatson JW, Maass DL, Wolf SE, Minei JP, Wigginton JG. 17beta-Estradiol reappropriates mass lost to the hypermetabolic state in thermally injured rats. J Surg Res 2013; 181: 136-141
• 23 Holecek M. Muscle wasting in animal models of severe illness. Int J Exp Pathol 2012; 93: 157-171
• 24 Akabori H, Moeinpour F, Bland KI, Chaudry IH. Mechanism of the anti-inflammatory effect Of 17beta-estradiol on brain following trauma-hemorrhage. Shock 2010; 33: 43-48
• 25 Miller M, Keith J, Berman J, Burlington DB, Grudzinskas C, Hubbard W, Peck C, Scott C, Chaudry IH. Efficacy of 17alpha-ethynylestradiol-3-sulfate for severe hemorrhage in minipigs in the absence of fluid resuscitation. J Trauma Acute Care Surg 2014; 76: 1409-1416
• 26 Chen Q, Li N, Zhu W, Li W, Tang S, Yu W, Gao T, Zhang J, Li J. Insulin alleviates degradation of skeletal muscle protein by inhibiting the ubiquitin-proteasome system in septic rats. J Inflam 2011; 8: 13
• 27 Spratt DI, Morton JR, Kramer RS, Mayo SW, Longcope C, Vary CP. Increases in serum estrogen levels during major illness are caused by increased peripheral aromatization. Am J Physiol Endocrinol Metab 2006; 291: E631-E638
• 28 Wichmann MW, Inthorn D, Andress HJ, Schildberg FW. Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Inten Care Med 2000; 26: 167-172
• 29 Offner PJ, Moore EE, Biffl WL. Male gender is a risk factor for major infections after surgery. Arch Surg (Chicago, IL: 1960) 1999; 134: 935-938 discussion 938–940
• 30 Trentzsch H, Nienaber U, Behnke M, Lefering R, Piltz S. Female sex protects from organ failure and sepsis after major trauma haemorrhage. Injury 2014; 45 (Suppl. 03) S20-S28
• 31 Sakr Y, Elia C, Mascia L, Barberis B, Cardellino S, Livigni S, Fiore G, Filippini C, Ranieri VM. The influence of gender on the epidemiology of and outcome from severe sepsis. Crit Care (London, England) 2013; 17: R50
• 32 Eachempati SR, Hydo L, Barie PS. Gender-based differences in outcome in patients with sepsis. Arch Surgery (Chicago, IL: 1960) 1999; 134: 1342-1347
• 33 Ribas V, Drew BG, Zhou Z, Phun J, Kalajian NY, Soleymani T, Daraei P, Widjaja K, Wanagat J, de Aguiar Vallim TQ, Fluitt AH, Bensinger S, Le T, Radu C, Whitelegge JP, Beaven SW, Tontonoz P, Lusis AJ, Parks BW, Vergnes L, Reue K, Singh H, Bopassa JC, Toro L, Stefani E, Watt MJ, Schenk S, Akerstrom T, Kelly M, Pedersen BK, Hewitt SC, Korach KS, Hevener AL. Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Sci Transl Med 2016; 8: 334ra354
• 34 Gao Q, Mezei G, Nie Y, Rao Y, Choi CS, Bechmann I, Leranth C, Toran-Allerand D, Priest CA, Roberts JL, Gao XB, Mobbs C, Shulman GI, Diano S, Horvath TL. Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med 2007; 13: 89-94
• 35 Burfeind KG, Michaelis KA, Marks DL. The central role of hypothalamic inflammation in the acute illness response and cachexia. Semin Cell Dev Biol 2016; 54: 42-52
• 36 Arruda AP, Milanski M, Romanatto T, Solon C, Coope A, Alberici LC, Festuccia WT, Hirabara SM, Ropelle E, Curi R, Carvalheira JB, Vercesi AE, Velloso LA. Hypothalamic actions of tumor necrosis factor a provide the thermogenic core for the wastage syndrome in cachexia. Endocrinology 2010; 151: 683-694
• 37 Rettew JA, Huet YM, Marriott I. Estrogens augment cell surface TLR4 expression on murine macrophages and regulate sepsis susceptibility in vivo. Endocrinology 2009; 150: 3877-3884
• 38 Suzuki T, Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Bland KI, Chaudry IH. Estrogen receptor-alpha predominantly mediates the salutary effects of 17beta-estradiol on splenic macrophages following trauma-hemorrhage. Am J Physiol Cell Physiol 2007; 293: C978-C984
• 39 Hsieh YC, Frink M, Kawasaki T, Thobe BM, Choudhry MA, Schwacha MG, Bland KI, Chaudry IH. Downregulation of TLR4-dependent ATP production is critical for estrogen-mediated immunoprotection in Kupffer cells following trauma-hemorrhage. J Cell Physiol 2007; 211: 364-370
• 40 Scarlett JM, Jobst EE, Enriori PJ, Bowe DD, Batra AK, Grant WF, Cowley MA, Marks DL. Regulation of central melanocortin signaling by interleukin-1 beta. Endocrinology 2007; 148: 4217-4225
• 41 Scarlett JM, Zhu X, Enriori PJ, Bowe DD, Batra AK, Levasseur PR, Grant WF, Meguid MM, Cowley MA, Marks DL. Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretion by acute and chronic inflammation. Endocrinology 2008; 149: 4837-4845
• 42 Macia L, Viltart O, Delacre M, Sachot C, Heliot L, Di Santo JP, Wolowczuk I. Interleukin-7, a new cytokine targeting the mouse hypothalamic arcuate nucleus: role in body weight and food intake regulation. PloS One 2010; 5: e9953
• 43 Cheung WW, Mak RH. Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease. Am J Physiol Renal Physiol 2012; 303: F1315-F1324
• 44 Olofsson LE, Pierce AA, Xu AW. Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake. Proc Natl Acad Sci USA 2009; 106: 15932-15937
• 45 Titolo D, Cai F, Belsham DD. Coordinate regulation of neuropeptide Y and agouti-related peptide gene expression by estrogen depends on the ratio of estrogen receptor (ER) alpha to ERbeta in clonal hypothalamic neurons. Mol Endocrinol 2006; 20: 2080-2092
• 46 Giannoni E, Guignard L, Knaup Reymond M, Perreau M, Roth-Kleiner M, Calandra T, Roger T. Estradiol and progesterone strongly inhibit the innate immune response of mononuclear cells in newborns. Infect Immun 2011; 79: 2690-2698