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AGE

, 38:33 | Cite as

Effects of aerobic training on markers of autophagy in the elderly

  • Yubisay Mejías-Peña
  • Paula Rodriguez-Miguelez
  • Rodrigo Fernandez-Gonzalo
  • Susana Martínez-Flórez
  • Mar Almar
  • José A. de Paz
  • María J. Cuevas
  • Javier González-GallegoEmail author
Article

Abstract

Autophagy is a molecular process essential for the maintenance of cellular homeostasis, which appears to (i) decline with age and (ii) respond to physical exercise. In addition, recent evidence suggests a crosstalk between autophagy and toll-like receptor (TLR)-associated inflammatory responses. This study assessed the effects of aerobic exercise training on autophagy and TLR signaling in older subjects. Twenty-nine healthy women and men (age, 69.7 ± 1.0 year) were randomized to a training (TG) or a control (CG) group. TG performed an 8-week aerobic training program, while CG followed their daily routines. Peripheral blood mononuclear cells were isolated from blood samples obtained before and after the intervention, and protein levels of protein 1 light chain 3 (LC3), sequestosome 1 (p62/SQSTM1), beclin-1, phosphorylated unc-51-like kinase (ULK-1), ubiquitin-like autophagy-related (Atg)12, Atg16, and lysosome-associated membrane protein (LAMP)-2 were measured. TLR2 and TLR4 signaling pathways were also analyzed. Peak oxygen uptake increased in TG after the intervention. Protein expression of beclin-1, Atg12, Atg16, and the LC3II/I ratio increased following the training program (p < 0.05), while expression of p62/SQSTM1 and phosphorylation of ULK-1 at Ser757 were lower (p < 0.05). Protein content of TLR2, TLR4, myeloid differentiation primary response gen 88 (MyD88), and TIR domain-containing adaptor-inducing interferon (TRIF) were not significantly modified by exercise. The current data indicate that aerobic exercise training induces alterations in multiple markers of autophagy, which seem to be unrelated to changes in TLR2 and TLR4 signaling pathways. These results expand knowledge on exercise-induced autophagy adaptations in humans and suggest that the exercise type employed may be a key factor explaining the potential relationship between autophagy and TLR pathways.

Keywords

Elderly Autophagy High-intensity interval training TLR 

Notes

Acknowledgments

This study was supported by Plan Nacional I + D + I DEP2013-47659-R, Spain. YM is a fellow from the University de Los Andes, Venezuela.

References

  1. Barth S, Glick D, Macleod KF (2010) Autophagy: assays and artifacts. J Pathol 221:117–124CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bayod S, Del Valle J, Pelegri C, Vilaplana J, Canudas AM, Camins A, et al. (2014) Macroautophagic process was differentially modulated by long-term moderate exercise in rat brain and peripheral tissues. J Physiol Pharmacol 65:229–239PubMedGoogle Scholar
  3. Bonilla DL, Bhattacharya A, Sha Y, Xu Y, Xiang Q, Kan A, Jagannath C, Komatsu M, Eissa NT (2013) Autophagy regulates phagocytosis by modulating the expression of scavenger receptors. Immunity 39:537–547CrossRefPubMedGoogle Scholar
  4. Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368:651–662CrossRefPubMedGoogle Scholar
  5. Cuervo AM, Macian F (2014) Autophagy and the immune function in aging. Curr Opin Immunol 29:97–104CrossRefPubMedGoogle Scholar
  6. Cuevas MJ, Almar M, García-Glez JC, García-López D, De Paz JA, Alvear-Ordenes I, et al. (2005) Changes in oxidative stress markers and NF-kappaB activation induced by sprint exercise. Free Radic Res 39:431–439CrossRefPubMedGoogle Scholar
  7. Fernandez-Gonzalo R, De Paz JA, Rodriguez-Miguelez P, Cuevas MJ, González-Gallego J (2012) Effects of eccentric exercise on toll-like receptor 4 signaling pathway in peripheral blood mononuclear cells. J Appl Physiol 112:2011–2018CrossRefPubMedGoogle Scholar
  8. Fernandez-Gonzalo R, De Paz JA, Rodriguez-Miguelez P, Cuevas MJ, González-Gallego J (2014) TLR4-mediated blunting of inflammatory responses to eccentric exercise in young women. Mediat Inflamm 2014:479395CrossRefGoogle Scholar
  9. Gleeson M, McFarlin B, Flynn M (2006) Exercise and toll-like receptors. Exerc Immunol Rev 12:34–53PubMedGoogle Scholar
  10. He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, Loh J, Fisher J, et al. (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481:511–515CrossRefPubMedPubMedCentralGoogle Scholar
  11. Huang J, Xu J, Pang S, Bai B, Yan B (2012) Age-related decrease of the LAMP-2 gene expression in human leukocytes. Clin Biochem 45:1229–1232CrossRefPubMedGoogle Scholar
  12. Into T, Inomata M, Niida S, Murakami Y, Shibata K (2010) Regulation of MyD88 aggregation and the MyD88-dependent signaling pathway by sequestosome 1 and histone deacetylase 6. J Biol Chem 285:35759–35769CrossRefPubMedPubMedCentralGoogle Scholar
  13. Into T, Inomata M, Takayama E, Takigawa T (2012) Autophagy in regulation of toll-like receptor signaling. Cell Signal 24:1150–1162CrossRefPubMedGoogle Scholar
  14. Jamart C, Francaux M, Millet GY, Deldicque L, Frère D, Féasson L (2012) Modulation of autophagy and ubiquitin–proteasome pathways during ultra-endurance running. J Appl Physiol 112:1529–1537CrossRefPubMedGoogle Scholar
  15. Kim J, Kundu M, Viollet B, Kam KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of ULK-1. Nat Cell Biol 13:132–141CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kim YA, Kim YS, Oh SL, Kim HJ, Song W (2013) Autophagic response to exercise training in skeletal muscle with age. J Physiol Biochem 69:697–705CrossRefPubMedGoogle Scholar
  17. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, et al. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445–544CrossRefPubMedPubMedCentralGoogle Scholar
  18. Li H, Miao W, Ma J, Xv Z, Bo H, Li J, et al. (2016) Acute exercise-induced mithochondrial stress triggers an inflammatory responses in the myocardium via NLRP3 inflammasome activation with mitophagy. Oxidative Med Cell Longev. doi: 10.1155/2016/1987149 Google Scholar
  19. Lira VA, Okutsu M, Zhang M, Greene NP, Laker RC, Breen DS, et al. (2013) Autophagy is required for exercise training induced skeletal muscle adaptation and improvement of physical performance. FASEB J 27:4184–4193CrossRefPubMedPubMedCentralGoogle Scholar
  20. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217CrossRefPubMedPubMedCentralGoogle Scholar
  21. Luo L, Lu AM, Wang Y, Hong A, Chen Y, Hu J, et al. (2013) Chronic resistance training activates autophagy and reduces apoptosis of muscle cells by modulating IGF-1 and its receptors, akt/mTOR and akt/FOXO3a signaling in aged rats. Exp Gerontol 48:427–436CrossRefPubMedGoogle Scholar
  22. Moller AB, Vendelbo MH, Christensen B, Clasen BF, Bak AM, Jørgensen JO, et al. (2015) Physical exercise increases autophagic signaling through ULK-1 in human skeletal muscle. J Appl Physiol 118:971–979CrossRefPubMedGoogle Scholar
  23. Nakatogawa H, Ichimura Y, Ohsumi Y (2007) Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130:165–178CrossRefPubMedGoogle Scholar
  24. Netea-Maier RT, Plantinga TS, Van De Veerdonk FL, Smit JW, Netea MG (2015) Modulation of inflammation by autophagy: consequences for human disease. Autophagy. doi: 10.1080/15548627.2015.1071759 PubMedGoogle Scholar
  25. Nickel T, Hanssen H, Emslander I, Drexel V, Hertel G, Schmidt-Trucksass A, et al. (2011) Immunomodulatory effects of aerobic training in obesity. Mediat Inflamm 2011:308965CrossRefGoogle Scholar
  26. Oh JE, Lee HK (2013) Autophagy as an immune modulator. Immun Netw 13:1–9CrossRefGoogle Scholar
  27. Pagano AF, Py G, Bernardi H, Candau RB, Sanchez AM (2014) Autophagy and protein turnover signaling in slow-twitch muscle during exercise. Med Sci Sports Exerc 46:1314–1325CrossRefPubMedGoogle Scholar
  28. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, et al. (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282:24131–24145CrossRefPubMedGoogle Scholar
  29. Peeri M, Amiri S (2015) Protective effects of exercise in metabolic disorders are mediated by inhibition of mitochondrial-derived sterile inflammation. Med Hypotheses 85:707–709CrossRefPubMedGoogle Scholar
  30. Reyna SM, Tantiwong P, Cersosimo E, Defronzo RA, Sriwijitkamol A, Musi N (2013) Short-term exercise training improves insulin sensitivity but does not inhibit inflammatory pathways in immune cells from insulin-resistant subjects. J Diabetes Res 2013:107805CrossRefPubMedPubMedCentralGoogle Scholar
  31. Rodriguez-Miguélez P, Fernandez-Gonzalo R, Almar M, Mejías Y, Rivas A, de Paz JA, et al. (2014) Role of toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects. Age (Dordr) 36:9734CrossRefGoogle Scholar
  32. Rodriguez-Miguelez P, Fernandez-Gonzalo R, Collado PS, Almar M, Martinez-Florez S, de Paz JA, et al. (2015) Whole-body vibration improves the anti-inflammatory status in elderly subjects through toll-like receptor 2 and 4 signaling pathways. Mech Ageing Dev 150:12–19CrossRefPubMedGoogle Scholar
  33. Sanchez AM, Bernardi H, Py G, Candau RB (2014) Autophagy is essential to support skeletal muscle plasticity in response to endurance exercise. Am J Physiol Regul Integr Comp Physiol 307:R956–R969CrossRefPubMedGoogle Scholar
  34. San-Miguel B, Crespo I, Sanchez DI, González-Fernández B, Ortiz de Urbina J, Tuñón MJ, et al. (2015) Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis. J Pineal Res 59:151–162CrossRefPubMedGoogle Scholar
  35. San-Miguel B, Crespo I, Vallejo D, Ortiz de Urbina J, Álvarez M, Tuñón MJ, et al. (2014) Melatonin modulates the autophagic response in acute liver failure induced by the rabbit hemorrhagic disease virus. J Pineal Res 56:313–321CrossRefPubMedGoogle Scholar
  36. Schwalm C, Jamart C, Benoit N, Naslain D, Premont C, Prevet J, et al. (2015) Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. FASEB J 29:3515–3526CrossRefPubMedGoogle Scholar
  37. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH (2012) Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13:255–263CrossRefPubMedPubMedCentralGoogle Scholar
  38. Tam BT, Siu PM (2014) Autophagic cellular responses to physical exercise in skeletal muscle. Sports Med 44:625–640CrossRefPubMedGoogle Scholar
  39. Tam BT, Pei XM, Yu AP, Sin TK, Leung KK, Au KK, et al. (2015) Autophagic adaptation is associated with exercise-induced fibre-type shifting in skeletal muscle. Acta Physiol 214:221–236CrossRefGoogle Scholar
  40. Vainshtein A, Grumati P, Sandri M, Bonaldo P (2014) Skeletal muscle, autophagy, and physical activity: the ménage à trois of metabolic regulation in health and disease. J Mol Med (Berl) 92:127–137CrossRefGoogle Scholar
  41. Walczak M, Martens S (2013) Dissecting the role of the Atg12–Atg5–Atg16 complex during autophagosome formation. Autophagy 9:424–425CrossRefPubMedPubMedCentralGoogle Scholar
  42. Weng TP, Huang SC, Chuang YF, Wang JS (2013) Effects of interval and continuous exercise training on CD4 lymphocyte apoptotic and autophagic responses to hypoxic stress in sedentary men. PLoS One 13:e80248CrossRefGoogle Scholar
  43. Wohlgemuth SE, Lees HA, Marzetti E, Manini TM, Aranda JM, Daniels MJ (2011) An exploratory analysis of the effects of a weight loss plus exercise program on cellular quality control mechanisms in older overweight women. Rejuvenation Res 14:315–324CrossRefPubMedPubMedCentralGoogle Scholar
  44. Wohlgemuth SE, Seo AY, Marzetti E, Lees HA, Leeuwenburgh C (2010) Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp Gerontol 45:138–148CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zhao J, Braultt JJ, Schild A, Cao P, Sandri M, Schiaffino S, et al. (2007) FoxO3 coordinately activates protein degradation by the autophagy/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6:472–483CrossRefPubMedGoogle Scholar

Copyright information

© American Aging Association 2016

Authors and Affiliations

  • Yubisay Mejías-Peña
    • 1
  • Paula Rodriguez-Miguelez
    • 2
  • Rodrigo Fernandez-Gonzalo
    • 3
  • Susana Martínez-Flórez
    • 1
  • Mar Almar
    • 1
  • José A. de Paz
    • 1
  • María J. Cuevas
    • 1
  • Javier González-Gallego
    • 1
    Email author
  1. 1.Institute of Biomedicine (IBIOMED)University of LeónLeónSpain
  2. 2.Divisions of Clinical and Translational Sciences, Georgia Prevention Institute, Department of PediatricsAugusta UniversityAugustaUSA
  3. 3.Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden

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