, 36:9706 | Cite as

Exercise training enhanced SIRT1 longevity signaling replaces the IGF1 survival pathway to attenuate aging-induced rat heart apoptosis

  • Chao-Hung Lai
  • Tsung-Jung Ho
  • Wei-Wen Kuo
  • Cecilia-Hsuan Day
  • Pei-ying Pai
  • Li-Chin Chung
  • Po-Hsiang Liao
  • Feng-Huei Lin
  • En-Ting Wu
  • Chih-Yang HuangEmail author


Cardiovascular disease is the second leading cause of death (9.1 %) in Taiwan. Heart function deteriorates with age at a rate of 1 % per year. As society ages, we must study the serious problem of cardiovascular disease. SIRT1 regulates important cellular processes, including anti-apoptosis, neuronal protection, cellular senescence, aging, and longevity. In our previous studies, rats with obesity, high blood pressure, and diabetes exhibiting slowed myocardial performance and induced cell apoptosis were reversed via sports training through IGF1 survival signaling compensation. This study designed a set of experiments with rats, in aging and exercise groups, to identify changes in myocardial cell signaling transduction pathways. Three groups of three different aged rats, 3, 12, and 18 months old, were randomly divided into aging groups (C3, A12, and A18) and exercise groups (E3, AE12, and AE18). The exercise training consisted of swimming five times a week with gradual increases from the first week from 20 to 60 min for 12 weeks. After the sports training process was completed, tissue sections were taken to observe cell organization (hematoxylin and eosin (H&E) stain) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays) and to observe any changes in the myocardial tissues and proteins (Western blotting). The experimental results show that cardiomyocyte apoptotic pathway protein expression increased with age in the aging groups (C3, A12, and A18), with improvement in the exercise group (E3, AE12, and AE18). However, the expression of the pro-survival p-Akt protein decreased significantly with age and reduced performance. The IGF1R/PI3K/Akt survival pathway in the heart of young rats can indeed be increased through exercise training. As rats age, this pathway loses its original function, even with increasing upstream IGF1. However, levels of SIRT1 and its downstream target PGC-1α were found to increase with age and compensatory performance. Moreover, exercise training enhanced the SIRT longevity pathway compensation instead of IGF1 survival signaling to improve cardiomyocyte survival.


Aging Exercise training Apoptosis SIRT1 IGF1 survival signaling 



This study is supported in part by the Taiwan Department of Health Clinical Trial and Research Center for Excellence (DOH102-TD-B-111-004).


  1. Aiello VD, Binotto MA (2007) Myocardial remodeling in congenital heart disease. Arq Bras Cardiol 88(6):185–186CrossRefGoogle Scholar
  2. Bisercić M, Feutrier JY, Reeves PR (1991) Nucleotide sequences of the gnd genes from nine natural isolates of Escherichia coli: evidence of intragenic recombination as a contributing factor in the evolution of the polymorphic gnd locus. J Bacteriol 173(12):3894–3900PubMedPubMedCentralGoogle Scholar
  3. Bishopric NH, Andreka P, Slepak T, Webster KA (2001) Molecular mechanisms of apoptosis in the cardiac myocyte. Curr Opin Pharmacol 1(2):141–150PubMedCrossRefGoogle Scholar
  4. Boluyt M, Bing O, Lakatta E (1995) The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. Eur Heart J 16(suppl N):19–30PubMedCrossRefGoogle Scholar
  5. Brachmann CB, Sherman JM, Devine SE, Cameron EE, Pillus L, Boeke JD (1995) The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev 9(23):2888–2902PubMedCrossRefGoogle Scholar
  6. Catalucci D, Condorelli G (2006) Effects of Akt on cardiac myocytes location counts. Circ Res 99(4):339–341PubMedCrossRefGoogle Scholar
  7. Chang C, Zhang C, Zhao X, Kuang X, Tang H, Xiao X (2013) Differential regulation of mitogen-activated protein kinase signaling pathways in human with different types of mitral valvular disease. Journal of Surgical Research 181 (1):49–59. doi: 10.1016/j.jss.2012.05.028
  8. Cheitlin MD (2003) Cardiovascular physiology—changes with aging. Am J Geriatr Cardiol 12(1):9–13PubMedCrossRefGoogle Scholar
  9. Chen Hi H, Chiang IP, Jen CJ (1996) Exercise training increases acetylcholine-stimulated endothelium-derived nitric oxide release in spontaneously hypertensive rats. J Biomed Sci 3(6):454–460PubMedCrossRefGoogle Scholar
  10. Cheng SM, Ho TJ, Yang AL, Chen IJ, Kao CL, Wu FN, Lin JA, Kuo CH, Ou HC, Huang CY, Lee SD (2013) Exercise training enhances cardiac IGFI-R/PI3K/Akt and Bcl-2 family associated pro-survival pathways in streptozotocin-induced diabetic rats. Int J Cardiol 167(2):478–485. doi: 10.1016/j.ijcard.2012.01.031 PubMedCrossRefGoogle Scholar
  11. Conti V, Russomanno G, Corbi G, Filippelli A (2012) Exercise training in aging and diseases. Transl Med UniSa 3:74PubMedPubMedCentralGoogle Scholar
  12. Corbi G, Conti V, Russomanno G, Rengo G, Vitulli P, Ciccarelli AL, Filippelli A, Ferrara N (2012) Is physical activity able to modify oxidative damage in cardiovascular aging? Oxidative Med Cell Longev. doi: 10.1155/2012/728547, Artn 728547Google Scholar
  13. Corbi G, Conti V, Russomanno G, Longobardi G, Furgi G, Filippelli A, Ferrara N (2013) Adrenergic signaling and oxidative stress: a role for sirtuins? Front Physiol 4:324. doi: 10.3389/fphys.2013.00324 PubMedCrossRefPubMedCentralGoogle Scholar
  14. Crow MT, Mani K, Nam Y-J, Kitsis RN (2004) The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res 95(10):957–970PubMedCrossRefGoogle Scholar
  15. Czerski L, Nuñez G (2004) Apoptosome formation and caspase activation: is it different in the heart? J Mol Cell Cardiol 37(3):643–652PubMedCrossRefGoogle Scholar
  16. DeFronzo RA, Ferrannini E (1991) Insulin resistence. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atheroclerotic cardiovascular disease. Diabetes Care 14(3):173–194Google Scholar
  17. Eli R, Fasciano JA (2006) An adjunctive preventive treatment for heart disease and a set of diagnostic tests to detect it: Insulin-like growth factor-1 deficiency and cell membrane pathology are an inevitable cause of heart disease. Med Hypotheses 66(5):964–968PubMedCrossRefGoogle Scholar
  18. Ferrara N, Rinaldi B, Corbi G, Conti V, Stiuso P, Boccuti S, Rengo G, Rossi F, Filippelli A (2008) Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Res 11(1):139–150. doi: 10.1089/rej.2007.0576 PubMedCrossRefGoogle Scholar
  19. Fischer U, Steffens S, Frank S, Rainov NG, Schulze-Osthoff K, Kramm CM (2004) Mechanisms of thymidine kinase/ganciclovir and cytosine deaminase/5-fluorocytosine suicide gene therapy-induced cell death in glioma cells. Oncogene 24(7):1231–1243CrossRefGoogle Scholar
  20. Frye RA (1999) Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun 260(1):273–279PubMedCrossRefGoogle Scholar
  21. Giallauria F, Cirillo P, Lucci R, Pacileo M, D'agostino M, Maietta P, Vitelli A, Chiarielo M, Vigorito C (2009) Effects of excercise-based cardiac rehabilitation on high mobility group box-1 levels after acute myocardial infarction: rationale and design. J Cardiovasv Med (Hagerstown) 10(8):659–663Google Scholar
  22. Hobi A, Roy S, Vuille C, Perdrix J, Darioli R (2006) Evolution of cardiac risk factors management among patients aged 65 years and older with coronary artery disease]. Rev Méd Suisse 2(56):658PubMedGoogle Scholar
  23. Huang CY, Yang AL, Lin YM, Wu FN, Lin JA, Chan YS, Tsai FJ, Tsai CH, Kuo CH, Lee SD (2012) Anti-apoptotic and pro-survival effects of exercise training on hypertensive hearts. J Appl Physiol 112(5):883–891. doi: 10.1152/japplphysiol.00605.2011 PubMedCrossRefGoogle Scholar
  24. Jäger S, Handschin C, Pierre JS, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci 104(29):12017–12022PubMedCrossRefPubMedCentralGoogle Scholar
  25. Khang D, Lu J, Yao C, Haberstroh KM, Webster TJ (2008) The role of nanometer and sub-micron surface features on vascular and bone cell adhesion on titanium. Biomaterials 29(8):970–983PubMedCrossRefGoogle Scholar
  26. Khoynezhad A, Jalali Z, Tortolani AJ (2004) Apoptosis: pathophysiology and therapeutic implications for the cardiac surgeon. Ann Thorac Surg 78(3):1109–1118PubMedCrossRefGoogle Scholar
  27. Knutti D, Kralli A (2001) PGC-1, a versatile coactivator. Trends Endocrinol Metab 12(8):360–365PubMedCrossRefGoogle Scholar
  28. Kuo W-W, Wu C-H, Lee S-D, Lin JA, Chu C-Y, Hwang J-M, Ueng K-C, Chang M-H, Yeh Y-L, Wang C-J (2005) Second-hand smoke–induced cardiac fibrosis is related to the Fas death receptor apoptotic pathway without mitochondria-dependent pathway involvement in rats. Environ Health Perspect 113(10):1349PubMedCrossRefPubMedCentralGoogle Scholar
  29. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127(6):1109–1122PubMedCrossRefGoogle Scholar
  30. Lai H-C, Liu T-J, Ting C-T, Sharma PM, Wang PH (2003) Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway. Mol Cell Endocrinol 205(1):99–106PubMedCrossRefGoogle Scholar
  31. Latronico MVG, Costinean S, Lavitrano ML, Peschle C, Condorelli G (2004) Regulation of cell size and contractile function by AKT in cardiomyocytes. Ann N Y Acad Sci 1015(1):250–260. doi: 10.1196/annals.1302.021 PubMedCrossRefGoogle Scholar
  32. Lee S-D, Kuo W-W, Ho Y-J, Lin A-C, Tsai C-H, Wang H-F, Kuo C-H, Yang A-L, Huang C-Y, Hwang J-M (2008) Cardiac Fas-dependent and mitochondria-dependent apoptosis in ovariectomized rats. Maturitas 61(3):268–277PubMedCrossRefGoogle Scholar
  33. Lee S-D, Shyu W-C, Cheng I-S, Kuo C-H, Chan Y-S, Lin Y-M, Tasi C-Y, Tsai C-H, Ho T-J, Huang C-Y (2012) Effects of exercise training on cardiac apoptosis in obese rats. Nutr Metab Cardiovasc DisGoogle Scholar
  34. Lee S-D, Lai TW, Lin S-Z, Lin C-H, Hsu Y-H, Li C-Y, Wang H-J, Lee W, Su C-Y, Yu Y-L, Shyu W-C (2013) Role of stress-inducible protein-1 in recruitment of bone marrow derived cells into the ischemic brains. EMBO Mol Med 5(8):1227–1246. doi: 10.1002/emmm.201202258 PubMedCrossRefPubMedCentralGoogle Scholar
  35. Lin J, Wu H, Tarr PT, Zhang C-Y, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN (2002) Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418(6899):797–801PubMedCrossRefGoogle Scholar
  36. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1(6):361–370PubMedCrossRefGoogle Scholar
  37. Lin P-P, Hsieh Y-M, Kuo W-W, Lin Y-M, Yeh Y-L, Lin C-C, Tsai F-J, Tsai C-H, Huang C-Y, Tsai C-C (2013) Probiotic-fermented purple sweet potato yogurt activates compensatory IGF‑IR/PI3K/Akt survival pathways and attenuates cardiac apoptosis in the hearts of spontaneously hypertensive rats. Int J Mol Med 32(6):1319–1328PubMedGoogle Scholar
  38. Palmen M, Daemen MJAP, Bronsaer R, Dassen WRM, Zandbergen HR, Kockx M, Smits JFM, van der Zee R, Doevendans PA (2001) Cardiac remodeling after myocardial infarction is impaired in IGF-1 deficient mice. Cardiovasc Res 50(3):516–524. doi: 10.1016/s0008-6363(01)00237-1 PubMedCrossRefGoogle Scholar
  39. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5(11):897–907PubMedCrossRefGoogle Scholar
  40. Schwartzman RA, Cidlowski JA (1993) Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr Rev 14(2):133–151PubMedGoogle Scholar
  41. Shoucri R (1991) Pump function of the heart as an optimal control problem. J Biomed Eng 13(5):384–390PubMedCrossRefGoogle Scholar
  42. Suchankova G, Nelson LE, Gerhart-Hines Z, Kelly M, Gauthier M-S, Saha AK, Ido Y, Puigserver P, Ruderman NB (2009) Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun 378(4):836–841PubMedCrossRefPubMedCentralGoogle Scholar
  43. Sugden PH, Clerk A (1998) Cellular mechanisms of cardiac hypertrophy. J Mol Med 76(11):725–746PubMedCrossRefGoogle Scholar
  44. Tezuka F, Takahashi T (1976) Pathology of cardiac hypertrophy in pressure overload. Jpn Circ J 40(10)Google Scholar
  45. Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA (2004) Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 94(4):514–524PubMedCrossRefGoogle Scholar
  46. Trask AJ, Delbin MA, Katz PS, Zanesco A, Lucchesi PA (2012) Differential coronary resistance microvessel remodeling between type 1 and type 2 diabetic mice: impact of excercise training. Vascul Pharmacol 57(5–6):187–193Google Scholar
  47. van Tol BAF, Huijsmans RJ, Kroon DW, Schothorst M, Kwakkel G (2006) Effects of exercise training on cardiac performance, exercise capacity and quality of life in patients with heart failure: a meta-analysis. Eur J Heart Fail 8(8):841–850. doi: 10.1016/j.ejheart.2006.02.013 PubMedCrossRefGoogle Scholar
  48. Yamamura T, Otani H, Nakao Y, Hattori R, Osako M, Imamura H (2001) IGF-I differentially regulates Bcl-xL and Bax and confers myocardial protection in the rat heart. Am J Physiol-Heart Circ Physiol 280(3):H1191–H1200PubMedGoogle Scholar
  49. Yin FC, Spurgeon HA, Rakusan K, Weisfeldt ML, Lakatta EG (1982) Use of tibial length to quantify cardiac hypertrophy: application in the aging rat. Am J Physiol Heart Circ Physiol 243(6):H941–H947Google Scholar

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • Chao-Hung Lai
    • 1
    • 2
  • Tsung-Jung Ho
    • 3
    • 4
  • Wei-Wen Kuo
    • 5
  • Cecilia-Hsuan Day
    • 6
  • Pei-ying Pai
    • 7
  • Li-Chin Chung
    • 8
  • Po-Hsiang Liao
    • 9
  • Feng-Huei Lin
    • 10
  • En-Ting Wu
    • 11
  • Chih-Yang Huang
    • 9
    • 12
    • 13
    • 14
    Email author
  1. 1.Graduate Institute of Aging MedicineChina Medical UniversityTaichungTaiwan
  2. 2.Division of Cardiology, Department of Internal MedicineArmed Force Taichung General HospitalTaichungTaiwan
  3. 3.School of Chinese Medicine, College of Chinese MedicineChina Medical UniversityTaichungTaiwan
  4. 4.Chinese Medicine DepartmentChina Medical University Beijing HospitalTaichungTaiwan
  5. 5.Department of Biological Science and TechnologyChina Medical UniversityTaichungTaiwan
  6. 6.Department of NursingMeiho UniversityPingtungTaiwan
  7. 7.Division of CardiologyChina Medical University HospitalTaichungTaiwan
  8. 8.Department of Hospital and Health Care AdministrationChia Nan University of Pharmacy & ScienceTainan CountyTaiwan
  9. 9.Graduate Institute of Basic Medical ScienceChina Medical UniversityTaichungTaiwan
  10. 10.Department of Healthcare AdministrationAsia UniversityTaichungTaiwan
  11. 11.Graduate Institute of Life SciencesNational Chung Hsing UniversityTaichungTaiwan
  12. 12.Graduate Institute of Chinese Medical ScienceChina Medical UniversityTaichungTaiwan
  13. 13.Department of Health and Nutrition BiotechnologyAsia UniversityTaichungTaiwan
  14. 14.Graduate Institute of Basic Medical Science, Graduate Institute of Chinese Medical ScienceChina Medical University and HospitalTaichungTaiwan

Personalised recommendations