Int J Sports Med 2010; 31(9): 671-675
DOI: 10.1055/s-0029-1246140
Genetics & Molecular Biology

© Georg Thieme Verlag KG Stuttgart · New York

Exercise Effects on Methylation of ASC Gene

K. Nakajima1 , 7 , M. Takeoka1 , M. Mori2 , S. Hashimoto3 , A. Sakurai4 , H. Nose5 , K. Higuchi2 , N. Itano1 , M. Shiohara6 , T. Oh7 , S. Taniguchi1
  • 1Department of Molecular Oncology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • 2Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • 3Preventive Medical Center, Shinshu University Hospital, Matsumoto, Japan
  • 4Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
  • 5Department of Sports Medical Sciences, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • 6Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
  • 7Department of Sports and Health Science, Faculty of Human Health Science, Matsumoto University, Matsumoto, Japan
Further Information

Publication History

accepted after revision December 06, 2009

Publication Date:
03 March 2010 (online)


Chronic moderate exercise has been reported to reduce pro-inflammatory cytokines. To analyze the molecular mechanisms by which training exerts these effects, the epigenetic influences of age and exercise on the ASC gene, which is responsible for IL-1β and IL-18 secretion, were investigated by ASC gene methylation. Further, the relationship between carcinogenesis and exercise, and methylation of the p15 tumor suppressive gene was also analyzed. High-intensity interval walking exercise, consisting of 3 min low-intensity walking at 40% of peak aerobic capacity followed by a 3 min high-intensity walking period above 70% of peak aerobic capacity, was continued for 6 months. Peripheral blood DNA extracts from young control (n=34), older control (n=153), and older exercise (n=230) groups were then analyzed by pyrosequencing for DNA methylation. Methylation of ASC decreased significantly with age (young control vs. older control, p<0.01), which is indicative of an age-dependent increase in ASC expression. Compared to the older control group, the degree of ASC methylation was higher in the older exercise group (older control vs. older exercise: p<0.01), and presumably lower ASC expression. Neither exercise nor age affected the methylation of the p15. In summary, chronic moderate exercise appears to attenuate the age-dependent decrease in ASC methylation, implying suppression of excess pro-inflammatory cytokines through reduction of ASC expression.


  • 1 Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D, Byun HM, Jiang J, Marinelli B, Pesatori AC, Bertazzi PA, Yang AS. Changes in DNA methylation patterns in subjects exposed to low-dose benzene.  Cancer Res. 2007;  67 876-880
  • 2 Calabró P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells.  Circulation. 2003;  108 1930-1932
  • 3 Casolini P, Catalani A, Zuena AR, Angelucci L. Inhibition of COX-2 reduces the age-dependent increase of hippocampal inflammatory markers, corticosterone secretion, and behavioral impairments in the rat.  J Neurosci Res. 2002;  68 337-343
  • 4 Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis.  N Engl J Med. 2001;  344 907-916
  • 5 Conway KE, McConnell BB, Bowring CE, Donald CD, Warren ST, Vertino PM. TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers.  Cancer Res. 2000;  60 6236-6242
  • 6 Dayan M, Segal R, Globerson A, Habut B, Shearer GM, Mozes E. Effect of aging on cytokine production in normal and experimental systemic lupus erythematosus-afflicted mice.  Exp Gerontol. 2000;  35 225-236
  • 7 England R, Pettersson M. Pyro Q-CpGTM: quantitative analysis of methylation in multiple CpG sites by Pyrosequencing®.  Nat Methods. 2005;  2 1-2
  • 8 Flynn MG, McFarlin BK, Phillips MD, Stewart LK, Timmerman KL. Toll-like receptor 4 and CD14 mRNA expression are lower in resistive exercise-trained elderly women.  J Appl Physiol. 2003;  95 1833-1842
  • 9 Gielen S, Adams V, Möbius-Winkler S, Linke A, Erbs S, Yu J, Kempf W, Schubert A, Schuler G, Hambrecht R. Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure.  J Am Coll Cardiol. 2003;  42 861-868
  • 10 Greiwe JS, Cheng B, Rubin DC, Yarasheski KE, Semenkovich CF. Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans.  FASEB J. 2001;  15 475-482
  • 11 Guan X, Sagara J, Yokoyama T, Koganehira Y, Oguchi M, Saida T, Taniguchi S. ASC/TMS1, a caspase-1 activating adaptor, is downregulated by aberrant methylation in human melanoma.  Int J Cancer. 2003;  107 202-208
  • 12 Harriss DJ, Atkinson G. International Journal of Sports Medicine – Ethical standards in sport and exercise science research.  Int J Sports Med. 2009;  30 701-702
  • 13 Malm C. Susceptibility to infections in elite athletes: the S-curve.  Scand J Med Sci Sports. 2006;  16 4-6
  • 14 Mariathasan S, Monack DM. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation.  Nat Rev Immunol. 2007;  7 31-40
  • 15 Masumoto J, Taniguchi S, Ayukawa K, Sarvotham H, Kishino T, Niikawa N, Hidaka E, Katsuyama T, Higuchi T, Sagara J. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells.  J Biol Chem. 1999;  274 33835-33838
  • 16 McFarlin BK, Flynn MG, Campbell WW, Craig BA, Robinson JP, Stewart LK, Timmerman KL, Coen PM. Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4.  J Gerontol A Biol Sci Med Sci. 2006;  61 388-393
  • 17 Nemoto K, Gen-no H, Masuki S, Okazaki K, Nose H. Effects of high-intensity interval walking training on physical fitness and blood pressure in middle-aged and older people.  Mayo Clin Proc. 2007;  82 803-811
  • 18 Nieman DC. Exercise, upper respiratory tract infection, and the immune system.  Med Sci Sports Exerc. 1994;  26 128-139
  • 19 O'Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K. Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production.  Clin Exp Immunol. 1998;  113 213-219
  • 20 Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6.  Physiol Rev.. 2008;  88 1379-1406
  • 21 Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.  Diabetes. 2003;  52 812-872
  • 22 Stehlik C, Lee SH, Dorfleutner A, Stassinopoulos A, Sagara J, Reed JC. Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation.  J Immunol. 2003;  171 6154-6163
  • 23 Stewart LK, Flynn MG, Campbell WW, Craig BA, Robinson JP, McFarlin BK, Timmerman KL, Coen PM, Felker J, Talbert E. Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4.  Brain Behav Immun. 2005;  19 389-397
  • 24 Taniguchi S, Sagara J. Regulatory molecules involved in inflammasome formation with special reference to a key mediator protein, ASC.  Semin Immunopathol. 2007;  29 231-238
  • 25 Taxman DJ, Zhang J, Champagne CB, Bergstralh DT, Iocca HA, Lich JD, Ting JP. Cutting edge: ASC mediates the induction of multiple cytokines by Porphyromonas gingivalis via caspase-1- dependent and -independent pathways.  J Immunol. 2006;  177 4252-4256
  • 26 Venkatraman JT, Rowland JA, Denardin E, Horvath PJ, Pendergast D. Influence of the level of dietary lipid intake and maximal exercise on the immune status in runners.  Med Sci Sports Exerc. 1997;  29 333-344
  • 27 Wang JS, Chang CY, Chow SE, Chen YW, Yang CM. Exercise modulates platelet-nasopharyngeal carcinoma cell aggregation and subsequent tissue factor and matrix metalloproteinase activities.  J Appl Physiol. 2007;  103 763-770
  • 28 Yamamoto M, Yaginuma K, Tsutsui H, Sagara J, Guan X, Seki E, Yasuda K, Yamamoto M, Akira S, Nakanishi K, Noda T, Taniguchi S. ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules.  Genes Cells. 2004;  9 1055-1067
  • 29 Yokoyama T, Sagara J, Guan, X, Masumoto J, Takeoka M, Komiyama Y, Miyata K, Higuchi K, Taniguchi S. Methylation of ASC/TMS1, a proapoptotic gene responsible for activating procaspase-1, in human colorectal cancer.  Cancer Lett. 2003;  202 101-108


Dr. Shun'ichiro Taniguchi

Department of Molecular

Oncology, (Institute on Aging and Adaptation)

Shinshu University Graduate

School of Medicine

3-1-1 Asahi

390 – 8621 Matsumoto


Phone: +81/263-37-2679

Fax: +81/263-37-2724