دورية أكاديمية

Chronic rapamycin treatment decreases hepatic IL-6 protein, but increases autophagy markers as a protective effect against the overtraining-induced tissue damage.

التفاصيل البيبلوغرافية
العنوان: Chronic rapamycin treatment decreases hepatic IL-6 protein, but increases autophagy markers as a protective effect against the overtraining-induced tissue damage.
المؤلفون: Pinto AP; Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil., da Rocha AL; Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil., Marafon BB; School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil., Nogueira JE; School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil., Branco LGS; Department of Basic and Oral Biology, Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil., Pauli JR; Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, Brazil., de Moura LP; Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, Brazil., Cintra DE; Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, Brazil., Ropelle ER; Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, Brazil., da Silva ASR; Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.; School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil.
المصدر: Clinical and experimental pharmacology & physiology [Clin Exp Pharmacol Physiol] 2022 Aug; Vol. 49 (8), pp. 893-902. Date of Electronic Publication: 2022 Jun 23.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: Australia NLM ID: 0425076 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1440-1681 (Electronic) Linking ISSN: 03051870 NLM ISO Abbreviation: Clin Exp Pharmacol Physiol Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford, England : Wiley-Blackwell
Original Publication: Oxford, Blackwell Scientific Publications.
مواضيع طبية MeSH: Interleukin-6* , Sirolimus*/pharmacology, Animals ; Autophagy ; Inflammation/metabolism ; Mammals/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Microtubule-Associated Proteins/metabolism
مستخلص: Regular endurance exercise is a non-pharmacological strategy to protect the liver against diseases. Conversely, exercise may be harmful when excessive, the so-called overtraining. As expected, mice who underwent an overtraining protocol presented higher levels of proinflammatory cytokines in the serum and liver. Based on the relationship among overtraining, inflammation and mammalian target of rapamycin complex 1 (mTORC1) upregulation, the present study verified if animals submitted to an overtraining protocol, but with inhibition of the mTOR pathway via rapamycin injections could mitigate the liver and serum inflammation. Once autophagy can be linked to the improvement of hepatic dysfunction, we also investigated if the inhibition of mTORC1 by rapamycin can improve hepatic autophagy. The animals were randomized into four groups: control (CT; sedentary mice), overtraining by downhill running (OT; mice submitted to the downhill running-based overtraining protocol), overtraining by downhill running with chronic administration of rapamycin (OT/Rapa; mice submitted to the downhill running-based overtraining protocol with intraperitoneal injections of rapamycin) and aerobic (AER; submitted to aerobic training protocol). The serum and liver of the animals were used for biochemical analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. The main results are (a) OT and OT/Rapa protocols decreased the performance; (b) the protein levels of interleukin 6 (IL-6) were higher for the OT group; the OT/Rapa group reduced the autophagic genes, increased the microtubule-associated protein light chain 3 II/I (LC3II/LC3I) protein ratio and decreased the sequestosome 1 (SQSTM1) protein. In conclusion, rapamycin appears efficiently to increase the autophagy proteins and decrease IL-6 protein in the liver of overtraining mice.
(© 2022 John Wiley & Sons Australia, Ltd.)
References: Kwon I, Song W, Jang Y, Choi MD, Vinci DM, Lee Y. Elevation of hepatic autophagy and antioxidative capacity by endurance exercise is associated with suppression of apoptosis in mice. Ann Hepatol. 2020;19(1):69-78.
Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 1985. 2005;98(4):1154-1162.
da Rocha AL, Pinto AP, Teixeira GR, et al. Exhaustive Training Leads to Hepatic Fat Accumulation. J Cell Physiol. 2017;232(8):2094-2103.
Pereira BC, Pauli JR, de Souza CT, et al. Nonfunctional overreaching leads to inflammation and myostatin upregulation in swiss mice. Int J Sports Med. 2014;35(2):139-146.
Pedersen BK. Muscle as a secretory organ. Compr Physiol. 2013;3(3):1337-1362.
Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol. 2016;64(6):1403-1415.
Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology. 1992;103(1):264-274.
Pinno J, Bongartz H, Klepsch O, et al. Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner. Cell Signal. 2016;28(8):907-916.
Chen S, van Tok MN, Knaup VL, et al. mTOR Blockade by Rapamycin in Spondyloarthritis: Impact on Inflammation and New Bone Formation. Front Immunol. 2019;10:2344.
Passos E, Pereira CD, Gonçalves IO, et al. Role of physical exercise on hepatic insulin, glucocorticoid and inflammatory signaling pathways in an animal model of non-alcoholic steatohepatitis. Life Sci. 2015;123:51-60.
Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330(6009):1344-1348.
Matsuzawa-Ishimoto Y, Hwang S, Cadwell K. Autophagy and Inflammation. Annu Rev Immunol. 2018;36:73-101.
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132-141.
Bai X, Wey MC, Fernandez E, et al. Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy. Pathobiol Aging Age Relat Dis. 2015;5:28743.
Bitto A, Ito TK, Pineda VV, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife. 2016;5:e16351.
Pereira BC, da Rocha AL, Pauli JR, et al. Excessive eccentric exercise leads to transitory hypothalamic inflammation, which may contribute to the low body weight gain and food intake in overtrained mice. Neuroscience. 2015;311:231-242.
Carmichael MD, Davis JM, Murphy EA, et al. Recovery of running performance following muscle-damaging exercise: relationship to brain IL-1beta. Brain Behav Immun. 2005;19(5):445-452.
da Rocha AL, Pinto AP, Pereira BC, et al. Positive effects of total recovery period on anti- and pro-inflammatory cytokines are not linked to performance re-establishment in overtrained mice. Cytokine. 2018;103:69-76.
Pinto AP, da Rocha AL, Pereira BC, et al. Excessive training is associated with endoplasmic reticulum stress but not apoptosis in the hypothalamus of mice. Appl Physiol Nutr Metab. 2017;42(4):354-360.
da Rocha AL, Pereira BC, Pauli JR, et al. Downhill Running-Based Overtraining Protocol Improves Hepatic Insulin Signaling Pathway without Concomitant Decrease of Inflammatory Proteins. PLoS One. 2015;10(10):e0140020.
Stallone G, Infante B, Grandaliano G, Gesualdo L. Management of side effects of sirolimus therapy. Transplantation. 2009;87(8 Suppl):S23-S26.
Yang SB, Lee HY, Young DM, et al. Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J Mol Med (Berl). 2012;90(5):575-585.
Ho E, Karimi Galougahi K, Liu CC, Bhindi R, Figtree GA. Biological markers of oxidative stress: Applications to cardiovascular research and practice. Redox Biol. 2013;1:483-491.
He F, Li J, Liu Z, Chuang CC, Yang W, Zuo L. Redox Mechanism of Reactive Oxygen Species in Exercise. Front Physiol. 2016;7:486.
Suzuki K, Tominaga T, Ruhee RT, Ma S. Characterization and Modulation of Systemic Inflammatory Response to Exhaustive Exercise in Relation to Oxidative Stress. Antioxidants (Basel). 2020;9(5):401.
Nogueira JE, Amorim MR, Pinto AP, da Rocha AL, da Silva ASR, Branco LGS. Molecular hydrogen downregulates acute exhaustive exercise-induced skeletal muscle damage. Can J Physiol Pharmacol. 2021;99(8):812-820.
Pedersen BK, Steensberg A, Fischer C, Keller C, Ostrowski K, Schjerling P. Exercise and cytokines with particular focus on muscle-derived IL-6. Exerc Immunol Rev. 2001;7:18-31.
Pedersen BK. The Physiology of Optimizing Health with a Focus on Exercise as Medicine. Annu Rev Physiol. 2019;81:607-627.
Ramadori G, Armbrust T. Cytokines in the liver. Eur J Gastroenterol Hepatol. 2001;13(7):777-784.
Kim JH, Kim JE, Liu HY, Cao W, Chen J. Regulation of interleukin-6-induced hepatic insulin resistance by mammalian target of rapamycin through the STAT3-SOCS3 pathway. J Biol Chem. 2008;283(2):708-715.
Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88(4):1379-1406.
Barrès R, Yan J, Egan B, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012;15(3):405-411.
Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013;17(2):162-184.
Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68.
Lu H, Han M, Yuan X, et al. Role of IL-6-mediated expression of NS5ATP9 in autophagy of liver cancer cells. J Cell Physiol. 2018;233(12):9312-9319.
Tang H, Fang H, Guo W, et al. Single nucleotide polymorphisms in interleukin-6 attenuates hepatocytes injury in hypoxia/re-oxygenation via STAT3 signal pathway mediated autophagy. Mol Biol Rep. 2021;48(2):1687-1695.
Pinto AP, da Rocha AL, Cabrera EMB, et al. Role of interleukin-6 in inhibiting hepatic autophagy markers in exercised mice. Cytokine. 2020;130:155085.
Zhang T, Yan J, Wang N, Dai L, Wang Y, Cai W. Autophagy May Protect Against Parenteral Nutrition-Associated Liver Disease by Suppressing Endoplasmic Reticulum Stress. JPEN J Parenter Enteral Nutr. 2019;43(1):96-106.
Lu Y, Cederbaum AI. Autophagy Protects against CYP2E1/Chronic Ethanol-Induced Hepatotoxicity. Biomolecules. 2015;5(4):2659-2674.
Farah BL, Landau DJ, Sinha RA, et al. Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency. J Hepatol. 2016;64(2):370-379.
Sun Y, Zou H, Yang L, et al. Effect on the liver cancer cell invasion ability by studying the associations between autophagy and TRAP1 expression. Oncol Lett. 2018;16(1):991-997.
Park HS, Song JW, Park JH, et al. TXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation. Autophagy. 2020;17:2549-2564.
Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy. 2021;17(1):1-382.
Loos B, du Toit A, Hofmeyr JH. Defining and measuring autophagosome flux-concept and reality. Autophagy. 2014;10(11):2087-2096.
Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1-222.
Umemura A, Park EJ, Taniguchi K, et al. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. 2014;20(1):133-144.
da Rocha AL, Pereira BC, Pauli JR, et al. Downhill Running Excessive Training Inhibits Hypertrophy in Mice Skeletal Muscles with Different Fiber Type Composition. J Cell Physiol. 2016;231(5):1045-1056.
Pereira BC, Filho LA, Alves GF, et al. A new overtraining protocol for mice based on downhill running sessions. Clin Exp Pharmacol Physiol. 2012;39(9):793-798.
Gurley JM, Griesel BA, Olson AL. Increased Skeletal Muscle GLUT4 Expression in Obese Mice After Voluntary Wheel Running Exercise Is Posttranscriptional. Diabetes. 2016;65(10):2911-2919.
Ferreira JC, Rolim NP, Bartholomeu JB, Gobatto CA, Kokubun E, Brum PC. Maximal lactate steady state in running mice: effect of exercise training. Clin Exp Pharmacol Physiol. 2007;34(8):760-765.
Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2016;12(1):1-222.
فهرسة مساهمة: Keywords: Autophagy; exercise; liver; mTORC1; rapamycin
المشرفين على المادة: 0 (Interleukin-6)
0 (Microtubule-Associated Proteins)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
W36ZG6FT64 (Sirolimus)
تواريخ الأحداث: Date Created: 20220531 Date Completed: 20220712 Latest Revision: 20220914
رمز التحديث: 20221213
DOI: 10.1111/1440-1681.13677
PMID: 35637552
قاعدة البيانات: MEDLINE
الوصف
تدمد:1440-1681
DOI:10.1111/1440-1681.13677