PHYSIOLOGY.ORG
Skip main navigation
Research Article

The role of interleukin-10 in mitigating endoplasmic reticulum stress in aged mice through exercise

Published Online:05 Sep 2024https://doi.org/10.1152/ajpendo.00204.2024

Abstract

Download figureDownload PowerPoint

Although unfolded protein response (UPR) is essential for cellular protection, its prolonged activation may induce apoptosis, compromising cellular longevity. The aging process increases the endoplasmic reticulum (ER) stress in skeletal muscle. However, whether combined exercise can prevent age-induced ER stress in skeletal muscle remains unknown. Evidence suggests that ER stress may increase inflammation by counteracting the positive effects of interleukin-10 (IL-10), whereas its administration in cells inhibits ER stress and apoptosis. This study verified the effects of aging and combined exercise on physical performance, ER stress markers, and inflammation in the quadriceps of mice. Moreover, we verified the effects of IL-10 on ER stress markers. C57BL/6 mice were distributed into young (Y, 6 mo old), old sedentary (OS, sedentary, 24 mo old), and old trained group (OT, submitted to short-term combined exercise, 24 mo old). To clarify the role of IL-10 in UPR pathways, knockout mice lacking IL-10 were used. The OS mice presented worse physical performance and higher ER stress-related proteins, such as C/EBP homologous protein (CHOP) and phospho-eukaryotic translation initiation factor 2 alpha (p-eIF2α/eIF2α). The exercise protocol increased muscle strength and IL-10 protein levels in OT while inducing the downregulation of CHOP protein levels compared with OS. Furthermore, mice lacking IL-10 increased BiP, CHOP, and p-eIF2α/eIF2α protein levels, indicating this cytokine can regulate the ER stress response in skeletal muscle. Bioinformatics analysis showed that endurance and resistance training downregulated DNA damage inducible transcript 3 (DDIT3) and XBP1 gene expression in the vastus lateralis of older people, reinforcing our findings. Thus, combined exercise is a potential therapeutic intervention for promoting adjustments in ER stress markers in aged skeletal muscle.

NEW & NOTEWORTHY Aging elevates endoplasmic reticulum (ER) stress in skeletal muscle, potentially heightening inflammation by opposing interleukin-10 (IL-10) effects. This study found that short-term combined exercise boosted strength and IL-10 protein levels while reducing CHOP protein levels in older mice. In addition, IL-10-deficient mice exhibited increased ER stress markers, highlighting IL-10’s role in regulating ER stress in skeletal muscle. Consequently, combined exercise emerges as a therapeutic intervention to elevate IL-10 and adjust ER stress markers in aging.

REFERENCES

  • 1. Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci 73: 79–94, 2016. doi:10.1007/s00018-015-2052-6.
    Crossref | PubMed | Web of Science | Google Scholar
  • 2. Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther 8: 352, 2023. doi:10.1038/s41392-023-01570-w.
    Crossref | PubMed | Web of Science | Google Scholar
  • 3. Brown MK, Naidoo N. The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol 3: 263, 2012. doi:10.3389/fphys.2012.00263.
    Crossref | PubMed | Web of Science | Google Scholar
  • 4. Estébanez B, de Paz JA, Cuevas MJ, González-Gallego J. Endoplasmic reticulum unfolded protein response, aging and exercise: an update. Front Physiol 9: 1744, 2018. doi:10.3389/fphys.2018.01744.
    Crossref | PubMed | Web of Science | Google Scholar
  • 5. Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529: 326–335, 2016. doi:10.1038/nature17041.
    Crossref | PubMed | Web of Science | Google Scholar
  • 6. da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, Rocha-Santos T. A synopsis on theories, mechanisms and future prospects. Ageing Res Rev 29: 90–112, 2016. doi:10.1016/j.arr.2016.06.005.
    Crossref | PubMed | Web of Science | Google Scholar
  • 7. Afroze D, Kumar A. ER stress in skeletal muscle remodeling and myopathies. FEBS J 286: 379–398, 2019. doi:10.1111/febs.14358.
    Crossref | PubMed | Web of Science | Google Scholar
  • 8. Miller MJ, Marcotte GR, Basisty N, Wehrfritz C, Ryan ZC, Strub MD, McKeen AT, Stern JI, Nath KA, Rasmussen BB, Judge AR, Schilling B, Ebert SM, Adams CM. The transcription regulator ATF4 is a mediator of skeletal muscle aging. Geroscience 45: 2525–2543, 2023. doi:10.1007/s11357-023-00772-y.
    Crossref | PubMed | Web of Science | Google Scholar
  • 9. Belaya I, Suwa M, Chen T, Giniatullin R, Kanninen KM, Atalay M, Kumagai S. Long-term exercise protects against cellular stresses in aged mice. Oxid Med Cell Longev 2018: 2894247, 2018. doi:10.1155/2018/2894247.
    Crossref | PubMed | Web of Science | Google Scholar
  • 10. Salminen A, Kaarniranta K, Kauppinen A. ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease. J Mol Med (Berl) 98: 633–650, 2020. doi:10.1007/s00109-020-01904-z.
    Crossref | PubMed | Web of Science | Google Scholar
  • 11. Junjappa RP, Patil P, Bhattarai KR, Kim HR, Chae HJ. IRE1alpha implications in endoplasmic reticulum stress-mediated development and pathogenesis of autoimmune diseases. Front Immunol 9: 1289, 2018. doi:10.3389/fimmu.2018.01289.
    Crossref | PubMed | Web of Science | Google Scholar
  • 12. Hansen IS, Schoonejans JM, Sritharan L, van Burgsteden JA, Ambarus CA, Baeten DLP, den Dunnen J. ER stress abrogates the immunosuppressive effect of IL-10 on human macrophages through inhibition of STAT3 activation. Inflamm Res 68: 775–785, 2019. doi:10.1007/s00011-019-01261-9.
    Crossref | PubMed | Web of Science | Google Scholar
  • 13. Malik A, Bagchi AK, Jassal DS, Singal PK. Interleukin-10 mitigates doxorubicin-induced endoplasmic reticulum stress as well as cardiomyopathy. Biomedicines 10: 775–785, 2022. doi:10.3390/biomedicines10040890.
    Crossref | PubMed | Web of Science | Google Scholar
  • 14. Marafon BB, Pinto AP, Ropelle ER, de Moura LP, Cintra DE, Pauli JR, da Silva ASR. Muscle endoplasmic reticulum stress in exercise. Acta Physiol (Oxf) 235: e13799, 2022. doi:10.1111/apha.13799.
    Crossref | PubMed | Web of Science | Google Scholar
  • 15. Izquierdo M, Merchant RA, Morley JE, Anker SD, Aprahamian I, Arai H, Aubertin-Leheudre M, Bernabei R, Cadore EL, Cesari M, Chen LK, de Souto Barreto P, Duque G, Ferrucci L, Fielding RA, García-Hermoso A, Gutiérrez-Robledo LM, Harridge SDR, Kirk B, Kritchevsky S, Landi F, Lazarus N, Martin FC, Marzetti E, Pahor M, Ramírez-Vélez R, Rodriguez-Mañas L, Rolland Y, Ruiz JG, Theou O, Villareal DT, Waters DL, Won Won C, Woo J, Vellas B, Fiatarone Singh M. International exercise recommendations in older adults (ICFSR): expert consensus guidelines. J Nutr Health Aging 25: 824–853, 2021. doi:10.1007/s12603-021-1665-8.
    Crossref | PubMed | Web of Science | Google Scholar
  • 16. Izquierdo M, Duque G, Morley JE. Physical activity guidelines for older people: knowledge gaps and future directions. Lancet Healthy Longev 2: e380–e383, 2021. doi:10.1016/S2666-7568(21)00079-9.
    Crossref | PubMed | Google Scholar
  • 17. Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, Li J. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther 7: 391, 2022. doi:10.1038/s41392-022-01251-0.
    Crossref | PubMed | Web of Science | Google Scholar
  • 18. Pinto AP, Muñoz VR, Tavares MEA, Dos Santos JR, Rebelo MA, Alberici LC, Simabuco FM, Teixeira GR, Pauli JR, de Moura LP, Cintra DE, Ropelle ER, Freitas EC, Rivas DA, da Silva ASR. Combined physical exercise reverses the reduced expression of Bmal1 in the liver of aged mice. Life Sci 312: 121175, 2023. doi:10.1016/j.lfs.2022.121175.
    Crossref | PubMed | Web of Science | Google Scholar
  • 19. Tavares MEA, Pinto AP, da Rocha AL, Sampaio LV, Correia RR, Batista VRG, Veras ASC, Chaves-Neto AH, da Silva ASR, Teixeira GR. Combined physical exercise re-synchronizes expression of Bmal1 and REV-ERBα and up-regulates apoptosis and metabolism in the prostate during aging. Life Sci 351: 122800, 2024. doi:10.1016/j.lfs.2024.122800.
    Crossref | PubMed | Google Scholar
  • 20. Da Rocha AL, Pereira BC, Pauli JR, De Souza CT, Teixeira GR, Lira FS, Cintra DE, Ropelle ER, Júnior CR, Da Silva AS. Downhill running excessive training inhibits hypertrophy in mice skeletal muscles with different fiber type composition. J Cell Physiol 231: 1045–1056, 2016. doi:10.1002/jcp.25197.
    Crossref | PubMed | Web of Science | Google Scholar
  • 21. Júnior CRB, Pantaleão LC, Voltarelli VA, Bozi LHM, Brum PC, Zatz M. Combined effect of AMPK/PPAR agonists and exercise training in mdx mice functional performance. PLoS One 7: e45699, 2012. doi:10.1371/journal.pone.0045699.
    Crossref | PubMed | Google Scholar
  • 22. de Melo DG, Anaruma CP, da Cruz Rodrigues KC, Pereira RM, de Campos TDP, Canciglieri RS, Ramos CO, Cintra DE, Ropelle ER, da Silva ASR, Pauli JR, de Moura LP. Strength training alters the tissue fatty acids profile and slightly improves the thermogenic pathway in the adipose tissue of obese mice. Sci Rep 12: 6913, 2022. doi:10.1038/s41598-022-10688-w.
    Crossref | PubMed | Web of Science | Google Scholar
  • 23. Pauli JR, Ropelle ER, Cintra DE, Carvalho-Filho MA, Moraes JC, De Souza CT, Velloso LA, Carvalheira JBC, Saad MJA. Acute physical exercise reverses S-nitrosation of the insulin receptor, insulin receptor substrate 1 and protein kinase B/Akt in diet-induced obese Wistar rats. J Physiol 586: 659–671, 2008. doi:10.1113/jphysiol.2007.142414.
    Crossref | PubMed | Web of Science | Google Scholar
  • 24. Kim JS, Yoon DH, Kim HJ, Choi MJ, Song W. Resistance exercise reduced the expression of fibroblast growth factor-2 in skeletal muscle of aged mice. Integr Med Res 5: 230–235, 2016. doi:10.1016/j.imr.2016.05.001.
    Crossref | PubMed | Web of Science | Google Scholar
  • 25. Liu Y, Chu JMT, Ran Y, Zhang Y, Chang RCC, Wong GTC. Prehabilitative resistance exercise reduces neuroinflammation and improves mitochondrial health in aged mice with perioperative neurocognitive disorders. J Neuroinflammation 19: 150, 2022. doi:10.1186/s12974-022-02483-1.
    Crossref | PubMed | Web of Science | Google Scholar
  • 26. Lee SR, Khamoui AV, Jo E, Park BS, Zourdos MC, Panton LB, Ormsbee MJ, Kim JS. Effects of chronic high-fat feeding on skeletal muscle mass and function in middle-aged mice. Aging Clin Exp Res 27: 403–411, 2015. doi:10.1007/s40520-015-0316-5.
    Crossref | PubMed | Web of Science | Google Scholar
  • 27. McMullan RC, Kelly SA, Hua K, Buckley BK, Faber JE, Pardo-Manuel de Villena F, Pomp D. Long-term exercise in mice has sex-dependent benefits on body composition and metabolism during aging. Physiol Rep 4: e13011, 2016. doi:10.14814/phy2.13011.
    Crossref | PubMed | Google Scholar
  • 28. Bei Y, Wang L, Ding R, Che L, Fan Z, Gao W, Liang Q, Lin S, Liu S, Lu X, Shen Y, Wu G, Yang J, Zhang G, Zhao W, Guo L, Xiao J. Animal exercise studies in cardiovascular research: current knowledge and optimal design-a position paper of the Committee on Cardiac Rehabilitation, Chinese Medical Doctors' Association. J Sport Health Sci 10: 660–674, 2021. doi:10.1016/j.jshs.2021.08.002.
    Crossref | PubMed | Web of Science | Google Scholar
  • 29. Whipple MO, Schorr EN, Talley KMC, Lindquist R, Bronas UG, Treat-Jacobson D. Variability in individual response to aerobic exercise interventions among older adults. J Aging Phys Act 26: 655–670, 2018. doi:10.1123/japa.2017-0054.
    Crossref | PubMed | Web of Science | Google Scholar
  • 30. Drey M, Krieger B, Sieber CC, Bauer JM, Hettwer S, Bertsch T; DISARCO Study Group. Motoneuron loss is associated with sarcopenia. J Am Med Dir Assoc 15: 435–439, 2014. doi:10.1016/j.jamda.2014.02.002.
    Crossref | PubMed | Web of Science | Google Scholar
  • 31. Booth FW, Roberts CK, Mj L. Lack of exercise is a major cause of chronic diseases. Compr Physiol 2: 1143–1211, 2012. doi:10.1002/cphy.c110025.
    Crossref | PubMed | Web of Science | Google Scholar
  • 32. Bianchi L, Volpato S. Muscle dysfunction in type 2 diabetes: a major threat to patient's mobility and independence. Acta Diabetol 53: 879–889, 2016. doi:10.1007/s00592-016-0880-y.
    Crossref | PubMed | Web of Science | Google Scholar
  • 33. Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14: 877–882, 2013. doi:10.1016/j.jamda.2013.05.009.
    Crossref | PubMed | Web of Science | Google Scholar
  • 34. Rygiel KA, Picard M, Turnbull DM. The ageing neuromuscular system and sarcopenia: a mitochondrial perspective. J Physiol 594: 4499–4512, 2016. doi:10.1113/JP271212.
    Crossref | PubMed | Web of Science | Google Scholar
  • 35. Bohnert KR, McMillan JD, Kumar A. Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. J Cell Physiol 233: 67–78, 2018. doi:10.1002/jcp.25852.
    Crossref | PubMed | Web of Science | Google Scholar
  • 36. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519–529, 2007. doi:10.1038/nrm2199.
    Crossref | PubMed | Web of Science | Google Scholar
  • 37. Ebert SM, Bullard SA, Basisty N, Marcotte GR, Skopec ZP, Dierdorff JM, Al-Zougbi A, Tomcheck KC, DeLau AD, Rathmacher JA, Bodine SC, Schilling B, Adams CM. Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ. J Biol Chem 295: 2787–2803, 2020. doi:10.1074/jbc.RA119.012095.
    Crossref | PubMed | Web of Science | Google Scholar
  • 38. Tamura Y, Matsunaga Y, Kitaoka Y, Hatta H. Effects of heat stress treatment on age-dependent unfolded protein response in different types of skeletal muscle. J Gerontol A Biol Sci Med Sci 72: 299–308, 2017. doi:10.1093/gerona/glw063.
    Crossref | PubMed | Web of Science | Google Scholar
  • 39. Chalil S, Pierre N, Bakker AD, Manders RJ, Pletsers A, Francaux M, Klein-Nulend J, Jaspers RT, Deldicque L. Aging related ER stress is not responsible for anabolic resistance in mouse skeletal muscle. Biochem Biophys Res Commun 468: 702–707, 2015. doi:10.1016/j.bbrc.2015.11.019.
    Crossref | PubMed | Web of Science | Google Scholar
  • 40. Brunner F, Schmid A, Sheikhzadeh A, Nordin M, Yoon J, Frankel V. Effects of aging on Type II muscle fibers: a systematic review of the literature. J Aging Phys Act 15: 336–348, 2007. doi:10.1123/japa.15.3.336.
    Crossref | PubMed | Web of Science | Google Scholar
  • 41. Schröder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res 569: 29–63, 2005. doi:10.1016/j.mrfmmm.2004.06.056.
    Crossref | PubMed | Web of Science | Google Scholar
  • 42. Hillary RF, FitzGerald U. A lifetime of stress: ATF6 in development and homeostasis. J Biomed Sci 25: 48, 2018. doi:10.1186/s12929-018-0453-1.
    Crossref | PubMed | Web of Science | Google Scholar
  • 43. Wu J, Ruas JL, Estall JL, Rasbach KA, Choi JH, Ye L, Boström P, Tyra HM, Crawford RW, Campbell KP, Rutkowski DT, Kaufman RJ, Spiegelman BM. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex. Cell Metab 13: 160–169, 2011. doi:10.1016/j.cmet.2011.01.003.
    Crossref | PubMed | Web of Science | Google Scholar
  • 44. Kim HJ, Jamart C, Deldicque L, An G-L, Lee YH, Kim CK, Raymackers J-M, Francaux M. ER-stress markers and ubiquitin-proteasome pathway activity in response to 200-km run. Med Sci Sports Exerc 43: 18–25, 2011. doi:10.1249/MSS.0b013e3181e4c5d1.
    Crossref | PubMed | Web of Science | Google Scholar
  • 45. Ogborn DI, McKay BR, Crane JD, Parise G, Tarnopolsky MA. The unfolded protein response is triggered following a single, unaccustomed resistance-exercise bout. Am J Physiol Regul Integr Comp Physiol 307: R664–R669, 2014. doi:10.1152/ajpregu.00511.2013.
    Link | Web of Science | Google Scholar
  • 46. Naidoo N. ER and aging—protein folding and the ER stress response. Ageing Res Rev 8: 150–159, 2009. doi:10.1016/j.arr.2009.03.001.
    Crossref | PubMed | Web of Science | Google Scholar
  • 47. Zhang J, Liang Y, Lin Y, Liu Y, You Y, Yin W. IRE1α-TRAF2-ASK1 pathway is involved in CSTMP-induced apoptosis and ER stress in human non-small cell lung cancer A549 cells. Biomed Pharmacother 82: 281–289, 2016. doi:10.1016/j.biopha.2016.04.050.
    Crossref | PubMed | Google Scholar
  • 48. Allagnat F, Fukaya M, Nogueira TC, Delaroche D, Welsh N, Marselli L, Marchetti P, Haefliger JA, Eizirik DL, Cardozo AK. C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in beta-cells. Cell Death Differ 19: 1836–1846, 2012. doi:10.1038/cdd.2012.67.
    Crossref | PubMed | Web of Science | Google Scholar
  • 49. Hofmann SR, Rösen-Wolff A, Tsokos GC, Hedrich CM. Biological properties and regulation of IL-10 related cytokines and their contribution to autoimmune disease and tissue injury. Clin Immunol 143: 116–127, 2012. doi:10.1016/j.clim.2012.02.005.
    Crossref | PubMed | Web of Science | Google Scholar
  • 50. Rong YD, Bian AL, Hu HY, Ma Y, Zhou XZ. Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10. BMC Geriatr 18: 308, 2018. doi:10.1186/s12877-018-1007-9.
    Crossref | PubMed | Web of Science | Google Scholar
  • 51. Jung K, Lee T, Kim J, Sung E, Song I. Interleukin-10 protects against ureteral obstruction-induced kidney fibrosis by suppressing endoplasmic reticulum stress and apoptosis. Int J Mol Sci 23: 10702, 2022. doi:10.3390/ijms231810702.
    Crossref | PubMed | Web of Science | Google Scholar
  • 52. Shkoda A, Ruiz PA, Daniel H, Kim SC, Rogler G, Sartor RB, Haller D. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology 132: 190–207, 2007. doi:10.1053/j.gastro.2006.10.030.
    Crossref | PubMed | Web of Science | Google Scholar
  • 53. Koriauli S, Natsvlishvili N, Barbakadze T, Mikeladze D. Knockdown of interleukin-10 induces the redistribution of sigma1-receptor and increases the glutamate-dependent NADPH-oxidase activity in mouse brain neurons. Biol Res 48: 55, 2015. doi:10.1186/s40659-015-0048-1.
    Crossref | PubMed | Web of Science | Google Scholar
  • 54. Pinto AP, da Rocha AL, Kohama EB, Gaspar RC, Simabuco FM, Frantz FG, de Moura LP, Pauli JR, Cintra DE, Ropelle ER, de Freitas EC, da Silva ASR. Exhaustive acute exercise-induced ER stress is attenuated in IL-6 knockout mice. J Endocrinol 240: 181–193, 2019. doi:10.1530/JOE-18-0404.
    Crossref | PubMed | Web of Science | Google Scholar
Previous
Back to Top
Next
Download PDF