Diabetes is closely connected with skeletal muscle dysfunction. Ellagic acid (EA) possesses a variety of bio-effects and is applied to the improvement of diabetes. The purpose of this study was to explore the potential improvement effect and mechanisms of EA in streptozotocin (STZ)-induced diabetic muscle atrophy. The model of diabetic mice was established by intra-peritoneal STZ to evaluate treatment effect of EA (100 mg/kg/d for 8 weeks) on muscle atrophy. Our data exhibited that EA enhanced fiber size and weight of gastrocnemius, and promoted grip strength to relieve STZ-induced muscle lesions. In serum, the levels of Creatine kinase (CK), lactate dehydrogenase (LDH), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL) were inhibited, while high-density lipoprotein cholesterol (HDL) level was enhanced by EA treatment in diabetic mice. In gastrocnemius, EA decreased Atrogin-1 and MuRF-1 expressions to relieve STZ-induced muscle atrophy. Moreover, EA increased NRF-1 and PGC-1alpha expressions to alleviate mitochondrial disorder. Meanwhile, EA suppressed CHOP and GRP-87 levels to relieve ER stress. Lastly, EA inhibited BAX expressions and enhanced Bcl-2 expressions to mitigate apoptosis. In conclusion, EA is preventing the event of STZ-induced gastrocnemia by amelioration of mitochondrial dysfunction, ER stress and apoptosis, and could be used in the protection and therapeutic of muscle atrophy in diabetes.

Faculty of Science College of Furong Hunan University of Arts and Science Changde China

Zobrazit více v PubMed

Holeček M. The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases. Physiol Res. 2021;70:293–305. doi: 10.33549/physiolres.934648. PubMed DOI PMC

Yaribeygi H, Farrokhi FR, Butler AE, Sahebkar A. Insulin resistance: Review of the underlying molecular mechanisms. J Cell Physiol. 2019;234:8152–8161. doi: 10.1002/jcp.27603. PubMed DOI

Huang DD, Shi G, Jiang Y, Yao C, Zhu C. A review on the potential of Resveratrol in prevention and therapy of diabetes and diabetic complications. Biomed Pharmacother. 2020;125:109767. doi: 10.1016/j.biopha.2019.109767. PubMed DOI

Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia. 2019;62:3–16. doi: 10.1007/s00125-018-4711-2. PubMed DOI

Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch. 2020;472:1273–1298. doi: 10.1007/s00424-020-02417-x. PubMed DOI PMC

Guo S, Chen Q, Sun Y, Chen J. Nicotinamide protects against skeletal muscle atrophy in streptozotocin-induced diabetic mice. Arch Physiol Biochem. 2019;125:470–477. doi: 10.1080/13813455.2019.1638414. PubMed DOI

Ishida T, Iizuka M, Ou Y, Morisawa S, Hirata A, Yagi Y, Jobu K, Morita Y, Miyamura M. Juzentaihoto Suppresses Muscle Atrophy in Streptozotocin-Induced Diabetic Mice. Biol Pharm Bull. 2019;42:1128–1133. doi: 10.1248/bpb.b18-00983. PubMed DOI

Zhang IX, Raghavan M, Satin LS. The endoplasmic reticulum and calcium homeostasis in pancreatic beta cells. Endocrinology. 2020;161:bqz028. doi: 10.1210/endocr/bqz028. PubMed DOI PMC

Romanello V, Sandri M. The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass. Cell Mol Life Sci. 2021;78:1305–1328. doi: 10.1007/s00018-020-03662-0. PubMed DOI PMC

Wang Y, Sun H, Zhang J, Xia Z, Chen W. Streptozotocin-induced diabetic cardiomyopathy in rats: ameliorative effect of PIPERINE via Bcl2, Bax/Bcl2, and caspase-3 pathways. Biosci Biotechnol Biochem. 2020;84:2533–2544. doi: 10.1080/09168451.2020.1815170. PubMed DOI

Amor AJ, Gómez-Guerrero C, Ortega E, Sala-Vila A, Lázaro I. Ellagic acid as a tool to limit the diabetes burden: Updated evidence. Antioxidants (Basel) 2020;9:1226. doi: 10.3390/antiox9121226. PubMed DOI PMC

Khodaei F, Rashedinia M, Heidari R, Rezaei M, Khoshnoud MJ. Ellagic acid improves muscle dysfunction in cuprizone-induced demyelinated mice via mitochondrial Sirt3 regulation. Life Sci. 2019;237:116954. doi: 10.1016/j.lfs.2019.116954. PubMed DOI

Harakeh S, Almuhayawi M, Jaouni SA, Almasaudi S, Hassan S, Amri TA, Azhar N, Abd-Allah E, Ali S, El-Shitany N, Mousa SA. Antidiabetic effects of novel ellagic acid nanoformulation: Insulin-secreting and anti-apoptosis effects. Saudi J Biol Sci. 2020;27:3474–3480. doi: 10.1016/j.sjbs.2020.09.060. PubMed DOI PMC

Akarca Dizakar SÖ, Saribas GS, Tekcan A. Effects of ellagic acid in the testes of streptozotocin induced diabetic rats. Drug Chem Toxicol. 2021:1–8. doi: 10.1080/01480545.2021.1908714. PubMed DOI

Ekinci Akdemir FN, Gülçin İ, Karagöz B, Soslu R, Alwasel SH. A comparative study on the antioxidant effects of hesperidin and ellagic acid against skeletal muscle ischemia/reperfusion injury. J Enzyme Inhib Med Chem. 2016;31(Sup4):114–118. doi: 10.1080/14756366.2016.1220378. PubMed DOI

Khodaei F, Rashedinia M, Heidari R, Rezaei M, Khoshnoud MJ. Ellagic acid improves muscle dysfunction in cuprizone-induced demyelinated mice via mitochondrial Sirt3 regulation. Life Sci. 2019;237:116954. doi: 10.1016/j.lfs.2019.116954. PubMed DOI

Chen H, Jin G. Downregulation of salusin-β protects renal tubular epithelial cells against high glucose-induced inflammation, oxidative stress, apoptosis and lipid accumulation via suppressing miR-155-5p. Bioengineered. 2021;12:6155–6165. doi: 10.1080/21655979.2021.1972900. PubMed DOI PMC

Yang J, Sun L, Fan X, Yin B, Kang Y, An S, Tang L. Pulsed electromagnetic fields alleviate streptozotocin induced diabetic muscle atrophy. Mol Med Rep. 2018;18:1127–1133. doi: 10.3892/mmr.2018.9067. PubMed DOI

Sun W, Li T, Yao H, Kang L, Dong F. Effects of concentrated growth factor and nanofat on aging skin of nude mice induced by D-galactose. Physiol Res. 2021;70:425–435. doi: 10.33549/physiolres.934640. PubMed DOI PMC

Yang W, Chen Y, Huang C, Wang W, Huang C, Li Y. MiR-18a Inhibits PI3K/AKT signaling pathway to regulate PDGF BB-induced airway smooth muscle cell proliferation and phenotypic transformation. Physiol Res. 2021;70:883–892. doi: 10.33549/physiolres.934753. PubMed DOI PMC

Klinge CM. Estrogenic control of mitochondrial function. Redox Biol. 2020;31:101435. doi: 10.1016/j.redox.2020.101435. PubMed DOI PMC

Nakamoto I, Ishihara A. Effects of voluntary running exercise on skeletal muscle properties in nonobese rats with type 2 diabetes. Physiol Res. 2020;69:73–84. doi: 10.33549/physiolres.934178. PubMed DOI PMC

Rana SVS. Endoplasmic reticulum stress induced by toxic elements-a review of recent developments. Biol Trace Elem Res. 2020;196:10–19. doi: 10.1007/s12011-019-01903-3. PubMed DOI

Geng H, Chen L, Su Y, Xu Q, Fan M, Huang R, Li X, Lu X, Pan M. miR-431-5p regulates apoptosis of cardiomyocytes after acute myocardial infarction via targeting selenoprotein T. Physiol Res. 2022;71:55–62. doi: 10.33549/physiolres.934683. PubMed DOI PMC

Merz KE, Thurmond DC. Role of skeletal muscle in insulin resistance and glucose uptake. Compr Physiol. 2020;10:785–809. doi: 10.1002/cphy.c190029. PubMed DOI PMC

Nankar RP, Doble M. Hybrid drug combination: anti-diabetic treatment of type 2 diabetic Wistar rats with combination of ellagic acid and pioglitazone. Phytomedicine. 2017;37:4–9. doi: 10.1016/j.phymed.2017.10.014. PubMed DOI

Tseng YT, Chang WH, Lin CC, Chang FR, Wu PC, Lo YC. Protective effects of Liuwei dihuang water extracts on diabetic muscle atrophy. Phytomedicine. 2019;53:96–106. doi: 10.1016/j.phymed.2018.09.032. PubMed DOI

Reddy SS, Shruthi K, Joy D, Reddy GB. 4-PBA prevents diabetic muscle atrophy in rats by modulating ER stress response and ubiquitin-proteasome system. Chem Biol Interact. 2019;306:70–77. doi: 10.1016/j.cbi.2019.04.009. PubMed DOI

Cheng TL, Lin ZY, Liao KY, Huang WC, Jhuo CF, Pan PH, Chen CJ, Kuan YH, Chen WY. Magnesium lithospermate B attenuates high-fat diet-induced muscle atrophy in C57BL/6J mice. Nutrients. 2021;14:104. doi: 10.3390/nu14010104. PubMed DOI PMC

Yin L, Chen X, Li N, Jia W, Wang N, Hou B, Yang H, Zhang L, Qiang G, Yang X, Du G. Puerarin ameliorates skeletal muscle wasting and fiber type transformation in STZ-induced type 1 diabetic rats. Biomed Pharmacother. 2021;133:110977. doi: 10.1016/j.biopha.2020.110977. PubMed DOI

Wang D, Sun H, Song G, Yang Y, Zou X, Han P, Li S. Resveratrol improves muscle atrophy by modulating mitochondrial quality control in STZ-induced diabetic mice. Mol Nutr Food Res. 2018;62:e1700941. doi: 10.1002/mnfr.201700941. PubMed DOI PMC

Joseph AM, Pilegaard H, Litvintsev A, Leick L, Hood DA. Control of gene expression and mitochondrial biogenesis in the muscular adaptation to endurance exercise. Essays Biochem. 2006;42:13–29. doi: 10.1042/bse0420013. PubMed DOI

Lira VA, Benton CR, Yan Z, Bonen A. PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab. 2010;299:E145–E161. doi: 10.1152/ajpendo.00755.2009. PubMed DOI PMC

Vainshtein A, Tryon LD, Pauly M, Hood DA. Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am J Physiol Cell Physiol. 2015;308:C710–C719. doi: 10.1152/ajpcell.00380.2014. PubMed DOI PMC

Akhtar S, Siragy HM. Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/PGC-1α pathway in diabetic kidney. PLoS One. 2019;14:e0225728. doi: 10.1371/journal.pone.0225728. PubMed DOI PMC

Park WY, Park J, Ahn KS, Kwak HJ, Um JY. Ellagic acid induces beige remodeling of white adipose tissue by controlling mitochondrial dynamics and SIRT3. FASEB J. 2021;35:e21548. doi: 10.1096/fj.202002491R. PubMed DOI

Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015;10:173–194. doi: 10.1146/annurev-pathol-012513-104649. PubMed DOI PMC

Delbrel E, Soumare A, Naguez A, Label R, Bernard O, Bruhat A, Fafournoux P, Tremblais G, Marchant D, Gille T, Bernaudin JF, Callard P, Kambouchner M, Martinod E, Valeyre D, Uzunhan Y, Planès C, Boncoeur E. HIF-1α triggers ER stress and CHOP-mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis. Sci Rep. 2018;8:17939. doi: 10.1038/s41598-018-36063-2. PubMed DOI PMC

Reddy SS, Shruthi K, Prabhakar YK, Sailaja G, Reddy GB. Implication of altered ubiquitin-proteasome system and ER stress in the muscle atrophy of diabetic rats. Arch Biochem Biophys. 2018;639:16–25. doi: 10.1016/j.abb.2017.12.015. PubMed DOI

Hseu YC, Chou CW, Senthil Kumar KJ, Fu KT, Wang HM, Hsu LS, Kuo YH, Wu CR, Chen SC, Yang HL. Ellagic acid protects human keratinocyte (HaCaT) cells against UVA-induced oxidative stress and apoptosis through the upregulation of the HO-1 and Nrf-2 antioxidant genes. Food Chem Toxicol. 2012;50:1245–1255. doi: 10.1016/j.fct.2012.02.020. PubMed DOI

Ono T, Takada S, Kinugawa S, Tsutsui H. Curcumin ameliorates skeletal muscle atrophy in type 1 diabetic mice by inhibiting protein ubiquitination. Exp Physiol. 2015;100:1052–1063. doi: 10.1113/EP085049. PubMed DOI

Bagheri F, Amri J, Salehi M, Karami H, Alimoradian A, Latifi SA. Effect of Artemisia absinthium ethanolic extract on oxidative stress markers and the TLR4, S100A4, Bax and Bcl-2 genes expression in the kidney of STZ-induced diabetic rats. Horm Mol Biol Clin Investig. 2020;41:10. doi: 10.1515/hmbci-2020-0028. PubMed DOI

Altamimi JZ, Alfaris NA, Alshammari GM, Alagal RI, Aljabryn DH, Aldera H, Alkhateeb MA, Yahya MA. Ellagic acid protects against diabetic cardiomyopathy in rats by stimulating cardiac silent information regulator 1 signaling. J Physiol Pharmacol. 2020;71:10. doi: 10.26402/jpp.2020.6.12. PubMed DOI

Aslan A, Beyaz S, Gok O, Erman O. The effect of ellagic acid on caspase-3/Bcl-2/Nrf-2/NF-kB/TNF-α/COX-2 gene expression product apoptosis pathway: a new approach for muscle damage therapy. Mol Biol Rep. 2020;47:2573–2582. doi: 10.1007/s11033-020-05340-7. PubMed DOI

Activation of Lactate Receptor Positively Regulates Skeletal Muscle Mass in Mice