Trehalose Protects against Insulin Resistance-Induced Tissue Injury and Excessive Autophagy in Skeletal Muscles and Kidney

Author(s): Wei Yu, Wenliang Zha, Hu Peng, Qiurong Wang, Shuning Zhang, Jun Ren*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 18 , 2019


Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: Insulin resistance refers to a pathological state of compromised sensitivity of insulin to promote glucose uptake and utilization, resulting in compensatory excessive insulin secretion and hyperinsulinemia in an effort to maintain glucose homeostasis. Akt2 represents an important member of the Akt family and plays an essential role in the maintenance of insulin signaling.

Methods: This study was designed to examine the effects of trehalose on kidney and skeletal muscle (rectus femoris muscle) injury in an Akt2 knockout-induced model of insulin resistance. Akt2 knockout (Akt2-/-) and adult WT mice were treated with trehalose (1 mg/g/d) intraperitoneally for 2 days, followed by providing 2% trehalose in drinking water for 2 months. Intraperitoneal glucose tolerance test (IPGTT), protein carbonyl content and mitochondrial function (aconitase activity) were examined. Apoptosis and autophagy protein markers were monitored using western blot analysis.

Results: Akt2 ablation impaired glucose tolerance, promoted protein carbonyl formation and decreased aconitase activity in kidney and skeletal muscles, associated with pronounced apoptosis and overt autophagy, the effects of which, with the exception of IPGTT, were greatly ameliorated or negated by trehalose treatment. Moreover, phosphorylation of mTOR was downregulated in both kidney and skeletal muscles from Akt2-/- mice, the effect of which was attenuated by trehalose. Levels of Akt (pan and Akt2) were much lower in Akt2-/- mice, the effect of which was unaffected by trehalose treatment although trehalose itself upregulated Akt levels.

Conclusion: These data suggest that the autophagy inducer trehalose rescued against insulin resistance-induced kidney and skeletal muscle injury, apoptosis and excessive autophagy, possibly in association with restored mTOR phosphorylation without affecting Akt.

Keywords: Akt2, trehalose, kidney, skeletal muscle, autophagy, apoptosis.

[1]
Sesti G. Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab 2006; 20(4): 665-79.
[http://dx.doi.org/10.1016/j.beem.2006.09.007] [PMID: 17161338]
[2]
Wang S, Ren J. Obesity paradox in aging: From prevalence to pathophysiology. Prog Cardiovasc Dis 2018; 61(2): 182-9.
[http://dx.doi.org/10.1016/j.pcad.2018.07.011] [PMID: 29990534]
[3]
Zhang Y, Whaley-Connell AT, Sowers JR, Ren J. Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management. Pharmacol Ther 2018; 191: 1-22.
[http://dx.doi.org/10.1016/j.pharmthera.2018.06.004] [PMID: 29909238]
[4]
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15(7): 539-53.
[http://dx.doi.org/10.1002/(SICI)1096-9136(199807)15:7<539:AID-DIA668>3.0.CO;2-S] [PMID: 9686693]
[5]
Hernández Bautista RJ, Mahmoud AM, Königsberg M, López Díaz Guerrero NE. Obesity: Pathophysiology, monosodium glutamate-induced model and anti-obesity medicinal plants. Biomed Pharmacother 2019; 111: 503-16.
[http://dx.doi.org/10.1016/j.biopha.2018.12.108] [PMID: 30597304]
[6]
Zhang Y, Ren J. Bridging the gap, facing the challenge-the 26(th) great wall international congress of cardiology (GW-ICC). Cardiovasc Diagn Ther 2016; 6(1): 97-100.
[PMID: 26885499]
[7]
Panzhinskiy E, Culver B, Ren J, et al. Role of mammalian target of rapamycin (mTOR) in muscle growth Nutrition and Enhanced Sports Performance. Elsevier Press 2013; 1: 251-61.
[8]
Bailey JL. Insulin resistance and muscle metabolism in chronic kidney disease. ISRN Endocrinol 2013; 2013: 329606.
[http://dx.doi.org/10.1155/2013/329606] [PMID: 23431467]
[9]
Pham H, Utzschneider KM, de Boer IH. Measurement of insulin resistance in chronic kidney disease. Curr Opin Nephrol Hypertens 2011; 20(6): 640-6.
[http://dx.doi.org/10.1097/MNH.0b013e32834b23c1] [PMID: 21885970]
[10]
Leslie NR. The redox regulation of PI 3-kinase-dependent signaling. Antioxid Redox Signal 2006; 8(9-10): 1765-74.
[http://dx.doi.org/10.1089/ars.2006.8.1765] [PMID: 16987030]
[11]
Wu C, Jiang F, Wei K, Jiang Z. Exercise activates the PI3K-AKT signal pathway by decreasing the expression of 5α-reductase type 1 in PCOS rats. Sci Rep 2018; 8(1): 7982.
[http://dx.doi.org/10.1038/s41598-018-26210-0] [PMID: 29789599]
[12]
Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005; 24(50): 7455-64.
[http://dx.doi.org/10.1038/sj.onc.1209085] [PMID: 16288292]
[13]
Gardner S, Anguiano M, Rotwein P. Defining Akt actions in muscle differentiation. Am J Physiol Cell Physiol 2012; 303(12): C1292-300.
[http://dx.doi.org/10.1152/ajpcell.00259.2012] [PMID: 23076793]
[14]
Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 2004; 9(6): 667-76.
[http://dx.doi.org/10.1023/B:APPT.0000045801.15585.dd] [PMID: 15505410]
[15]
Wang S, Zhu X, Xiong L, Ren J. Ablation of Akt2 prevents paraquat-induced myocardial mitochondrial injury and contractile dysfunction: Role of Nrf2. Toxicol Lett 2017; 269: 1-14.
[http://dx.doi.org/10.1016/j.toxlet.2017.01.009] [PMID: 28115273]
[16]
Lan A, Du J. Potential role of Akt signaling in chronic kidney disease. Nephrol Dial Transplant 2015; 30(3): 385-94.
[http://dx.doi.org/10.1093/ndt/gfu196] [PMID: 24891436]
[17]
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009; 27(13): 2278-87.
[http://dx.doi.org/10.1200/JCO.2008.20.0766] [PMID: 19332717]
[18]
Peng XD, Xu PZ, Chen ML, et al. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev 2003; 17(11): 1352-65.
[http://dx.doi.org/10.1101/gad.1089403] [PMID: 12782654]
[19]
Tan K, Kimber WA, Luan J, et al. Analysis of genetic variation in Akt2/PKB-beta in severe insulin resistance, lipodystrophy, type 2 diabetes, and related metabolic phenotypes. Diabetes 2007; 56(3): 714-9.
[http://dx.doi.org/10.2337/db06-0921] [PMID: 17327441]
[20]
Chen X, Al-Hasani H, Olausson T, Wenthzel AM, Smith U, Cushman SW. Activity, phosphorylation state and subcellular distribution of GLUT4-targeted Akt2 in rat adipose cells. J Cell Sci 2003; 116(Pt 17): 3511-8.
[http://dx.doi.org/10.1242/jcs.00675] [PMID: 12876218]
[21]
Cho H, Mu J, Kim JK, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001; 292(5522): 1728-31.
[http://dx.doi.org/10.1126/science.292.5522.1728] [PMID: 11387480]
[22]
Ren J, Zhang Y. Targeting Autophagy in Aging and Aging-Related Cardiovascular Diseases. Trends Pharmacol Sci 2018; 39(12): 1064-76.
[http://dx.doi.org/10.1016/j.tips.2018.10.005] [PMID: 30458935]
[23]
Wang S, Ren J. Role of autophagy and regulatory mechanisms in alcoholic cardiomyopathy. Biochim Biophys Acta Mol Basis Dis 2018; 1864(6 Pt A): 2003-9.
[http://dx.doi.org/10.1016/j.bbadis.2018.03.016] [PMID: 29555210]
[24]
Jia SN, Lin C, Chen DF, et al. The transcription factor p8 regulates autophagy in response to palmitic acid stress via a mammalian target of rapamycin (mTOR)-independent signaling pathway. J Biol Chem 2016; 291(9): 4462-72.
[http://dx.doi.org/10.1074/jbc.M115.675793] [PMID: 26733200]
[25]
Chen Q, Haddad GG. Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals. J Exp Biol 2004; 207(Pt 18): 3125-9.
[http://dx.doi.org/10.1242/jeb.01133] [PMID: 15299033]
[26]
Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007; 282(8): 5641-52.
[http://dx.doi.org/10.1074/jbc.M609532200] [PMID: 17182613]
[27]
Sciarretta S, Yee D, Nagarajan N, et al. Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction. J Am Coll Cardiol 2018; 71(18): 1999-2010.
[http://dx.doi.org/10.1016/j.jacc.2018.02.066] [PMID: 29724354]
[28]
Wang Q, Ren J. mTOR-Independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1. Pharmacol Res 2016; 111: 357-73.
[http://dx.doi.org/10.1016/j.phrs.2016.06.024] [PMID: 27363949]
[29]
Turdi S, Hu N, Ren J. Tauroursodeoxycholic acid mitigates high fat diet-induced cardiomyocyte contractile and intracellular Ca2+ anomalies. PLoS One 2013; 8(5): e63615.
[http://dx.doi.org/10.1371/journal.pone.0063615] [PMID: 23667647]
[30]
Zhu X, Jiang S, Hu N, et al. Tumour necrosis factor-α inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice. Clin Exp Pharmacol Physiol 2014; 41(7): 489-501.
[http://dx.doi.org/10.1111/1440-1681.12240] [PMID: 24739012]
[31]
Liu Y, Yuan J, Xiang L, et al. A high sucrose and high fat diet induced the development of insulin resistance in the skeletal muscle of Bama miniature pigs through the Akt/GLUT4 pathway. Exp Anim 2017; 66(4): 387-95.
[http://dx.doi.org/10.1538/expanim.17-0010] [PMID: 28674285]
[32]
Thomas SS, Zhang L, Mitch WE. Molecular mechanisms of insulin resistance in chronic kidney disease. Kidney Int 2015; 88(6): 1233-9.
[http://dx.doi.org/10.1038/ki.2015.305] [PMID: 26444029]
[33]
Verzola D, Bonanni A, Sofia A, et al. Toll-like receptor 4 signalling mediates inflammation in skeletal muscle of patients with chronic kidney disease. J Cachexia Sarcopenia Muscle 2017; 8(1): 131-44.
[http://dx.doi.org/10.1002/jcsm.12129] [PMID: 27897392]
[34]
Chen WS, Xu PZ, Gottlob K, et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 2001; 15(17): 2203-8.
[http://dx.doi.org/10.1101/gad.913901] [PMID: 11544177]
[35]
Xue XH, Feng ZH, Li ZX, Pan XY. Salidroside inhibits steroid-induced avascular necrosis of the femoral head via the PI3K/Akt signaling pathway: In vitro and in vivo studies. Mol Med Rep 2018; 17(3): 3751-7.
[PMID: 29286130]
[36]
Yoshizane C, Mizote A, Yamada M, et al. Glycemic, insulinemic and incretin responses after oral trehalose ingestion in healthy subjects. Nutr J 2017; 16(1): 9.
[http://dx.doi.org/10.1186/s12937-017-0233-x] [PMID: 28166771]
[37]
Pan H, Ding Y, Yan N, Nie Y, Li M, Tong L. Trehalose prevents sciatic nerve damage to and apoptosis of Schwann cells of streptozotocin-induced diabetic C57BL/6J mice. Biomed Pharmacother 2018; 105: 907-14.
[http://dx.doi.org/10.1016/j.biopha.2018.06.069] [PMID: 30021384]
[38]
Lin CF, Kuo YT, Chen TY, Chien CT. Quercetin-rich guava (Psidium guajava) juice in combination with trehalose reduces autophagy, apoptosis and pyroptosis formation in the kidney and pancreas of type II diabetic rats. Molecules 2016; 21(3): 334.
[http://dx.doi.org/10.3390/molecules21030334] [PMID: 26978332]
[39]
Singh R, Cuervo AM. Autophagy in the cellular energetic balance. Cell Metab 2011; 13(5): 495-504.
[http://dx.doi.org/10.1016/j.cmet.2011.04.004] [PMID: 21531332]
[40]
Pan Y, Yang XH, Guo LL, Gu YH, Qiao QY, Jin HM. Erythropoietin reduces insulin resistance via regulation of its receptor-mediated signaling pathways in db/db mice skeletal muscle. Int J Biol Sci 2017; 13(10): 1329-40.
[http://dx.doi.org/10.7150/ijbs.19752] [PMID: 29104499]
[41]
Grumati P, Bonaldo P. Autophagy in skeletal muscle homeostasis and in muscular dystrophies. Cells 2012; 1(3): 325-45.
[http://dx.doi.org/10.3390/cells1030325] [PMID: 24710479]
[42]
Fry CS, Drummond MJ, Lujan HL, DiCarlo SE, Rasmussen BB. Paraplegia increases skeletal muscle autophagy. Muscle Nerve 2012; 46(5): 793-8.
[http://dx.doi.org/10.1002/mus.23423] [PMID: 23055316]
[43]
He C, Bassik MC, Moresi V, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 2012; 481(7382): 511-5.
[http://dx.doi.org/10.1038/nature10758] [PMID: 22258505]
[44]
Wei W, An XR, Jin SJ, Li XX, Xu M. Inhibition of insulin resistance by PGE1 via autophagy-dependent FGF21 pathway in diabetic nephropathy. Sci Rep 2018; 8(1): 9.
[http://dx.doi.org/10.1038/s41598-017-18427-2] [PMID: 29311680]
[45]
Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000; 19(21): 5720-8.
[http://dx.doi.org/10.1093/emboj/19.21.5720] [PMID: 11060023]
[46]
Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005; 122(6): 927-39.
[http://dx.doi.org/10.1016/j.cell.2005.07.002] [PMID: 16179260]
[47]
Furuya D, Tsuji N, Yagihashi A, Watanabe N. Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp Cell Res 2005; 307(1): 26-40.
[http://dx.doi.org/10.1016/j.yexcr.2005.02.023] [PMID: 15922724]
[48]
Khalifeh M, Barreto GE, Sahebkar A. Trehalose as a promising therapeutic candidate for the treatment of Parkinson’s disease. Br J Pharmacol 2019; 176(9): 1173-89.
[http://dx.doi.org/10.1111/bph.14623] [PMID: 30767205]
[49]
Chou LF, Cheng YL, Hsieh CY, et al. Effect of trehalose supplementation on autophagy and cystogenesis in a mouse model of polycystic kidney disease. Nutrients 2018; 11(1): 11.
[http://dx.doi.org/10.3390/nu11010042] [PMID: 30585217]
[50]
Gao Z, Wang H, Zhang B, et al. Trehalose inhibits H2O2-induced autophagic death in dopaminergic SH-SY5Y cells via mitigation of ROS-dependent endoplasmic reticulum stress and AMPK activation. Int J Med Sci 2018; 15(10): 1014-24.
[http://dx.doi.org/10.7150/ijms.25656] [PMID: 30013443]
[51]
Lee BS, Oh J, Kang SK, et al. Insulin Protects Cardiac Myocytes from Doxorubicin Toxicity by Sp1-Mediated Transactivation of Survivin. PLoS One 2015; 10(8): e0135438.
[http://dx.doi.org/10.1371/journal.pone.0135438] [PMID: 26271039]
[52]
Wang ZG, Wang Y, Huang Y, et al. bFGF regulates autophagy and ubiquitinated protein accumulation induced by myocardial ischemia/reperfusion via the activation of the PI3K/Akt/mTOR pathway. Sci Rep 2015; 5: 9287.
[http://dx.doi.org/10.1038/srep09287] [PMID: 25787015]
[53]
Pasini E, Flati V, Paiardi S, et al. Intracellular molecular effects of insulin resistance in patients with metabolic syndrome. Cardiovasc Diabetol 2010; 9: 46.
[http://dx.doi.org/10.1186/1475-2840-9-46] [PMID: 20809949]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 25
ISSUE: 18
Year: 2019
Published on: 04 September, 2019
Page: [2077 - 2085]
Pages: 9
DOI: 10.2174/1381612825666190708221539
Price: $65

Article Metrics

PDF: 39
HTML: 9