Sports Medicine

, Volume 38, Issue 9, pp 715–733 | Cite as

Heat Shock Protein 72 Response to Exercise in Humans

  • Paulette Yamada
  • Fabiano Amorim
  • Pope Moseley
  • Suzanne Schneider
Review Article


Heat shock protein (Hsp) 72 is a unique, ubiquitous molecule. In vitro and in vivo animal models have shown that increased Hsp 72 is associated with improved cellular survivability and tolerance to stressors. The primary focus of this article is to review the Hsp 72 protein response to exercise in humans. Various mechanisms regulate post-transcriptional activity and therefore measurement of messenger RNA (mRNA) does not necessarily represent the level of functional Hsp 72. For this reason, this article incorporates only a few studies that assessed Hsp 72 mRNA response to exercise. Although this article focuses on human studies, it also includes some key animal studies to provide insight into the mechanisms of the response of Hsp 72 to stress.

Intra-(IC) and extracellular (EC) Hsp 72 have different functions. IC Hsp 72 confers cellular protection from subsequent stressors, while EC Hsp 72 has a whole-body systemic role in antigen presentation and immunity. An acute exercise bout stimulates an increase in both IC and EC Hsp 72. Long-term training and improved fitness increases the rate of availability of IC Hsp 72 in response to stress. Other factors that affect Hsp 72 production include environmental factors, exercise mode, duration and intensity, age, estrogen, and anti-oxidant and glycogen availability. The functions and roles of Hsp 72 also depend on the tissue of origin. This article describes the Hsp 72 response to exercise in relation to the tissue assayed (i.e. skeletal muscle vs lymphocyte) and the origin of the sample (i.e. venous vs arterial serum). Collectively, the reviewed studies reveal exciting and novel research that encourages future investigation in this area.


Skeletal Muscle Peripheral Blood Mononuclear Cell Muscle Damage Vastus Lateralis Extensor Digitorum Longus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No funding was received in the preparation of this article and the authors have no conflicts of interest directly relevant to its contents.


  1. 1.
    Fehrenbach E, Northoff H. Free radicals, exercise, apoptosis,and heat shock proteins. Exerc Immunol Rev 2001; 7: 66–89PubMedGoogle Scholar
  2. 2.
    Liu Y, Steinacker JM. Changes in skeletal muscle heat shock proteins: pathological significance. Front Biosci 2001; 6:12–25CrossRefGoogle Scholar
  3. 3.
    Moseley PL. Exercise, heat and thermotolerance: molecular mechanisms. In: Gisolfi C, Lamb D, Nadel E, editors. Perspectives in exercise science and sports medicine: exercise, heat,and thermoregulation. Traverse City (MI): Cooper Publishing Group, 2001: 305–34Google Scholar
  4. 4.
    Xu Q, Wick G. The role of heat shock proteins in protection and pathophysiology of the arterial wall. Mol Med Today 1996; 2: 372–9PubMedCrossRefGoogle Scholar
  5. 5.
    Jaattela M, Wissing D. Heat-shock proteins protect cells from monocyte cytotoxicity: possible mechanism of self-protection. J Exp Med 1993; 177: 231–6PubMedCrossRefGoogle Scholar
  6. 6.
    Kluger MJ, Rudolph K, Soszynski D, et al. Effect of heat stress on LPS-induced fever and tumor necrosis factor. Am J Physiol 1997; 273 (3 Pt 2): 858–63Google Scholar
  7. 7.
    Muller E, Munker R, Issels R, et al. Interaction between tumor necrosis factor-alpha and HSP 70 in human leukemia cells. Leuk Res 1993; 17: 523–6PubMedCrossRefGoogle Scholar
  8. 8.
    Lewis MJ, Pelham HR. Involvement of ATP in the nuclear and nucleolar functions of the 70 kd heat shock protein. Embo J 1985; 4 (12): 3137–43PubMedGoogle Scholar
  9. 9.
    Lee WC, Wen HC, Chang CP, et al. Heat shock protein 7 over expression protects against hyperthermia, circulatoryshock, and cerebral ischemia during heatstrok. J Appl Physiol 2006; 100: 2073–82PubMedCrossRefGoogle Scholar
  10. 10.
    Ianaro A, Ialenti A, Maffia P, et al. HSF1/hsp72 pathway as an endogenous anti-inflammatory system. FEBS Lett 2001; 499 (3): 239–44PubMedCrossRefGoogle Scholar
  11. 11.
    Moseley PL. The role of heat shock proteins in modulating the immune response. In: Locke M, Noble E, editors. Exercise and stress response: the role of stress proteins. Boca Raton (FL): CRC Press LLC, 2002: 179–95CrossRefGoogle Scholar
  12. 12.
    Febbraio MA, Ott P, Nielsen HB, et al. Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J Physiol 2002; 544 (Pt 3): 957–62PubMedCrossRefGoogle Scholar
  13. 13.
    Hung CH, Chang NC, Cheng BC, et al. Progressive exercise pre conditioning protects against circulatory shock during experimental heatstroke. Shock 2005; 23 (5): 426–33PubMedCrossRefGoogle Scholar
  14. 14.
    Skidmore R, Gutierrez JA, Guerriero Jr V, et al. HSP70 inducinduction during exercise and heat stress in rats: role of internal temperature. Am J Physiol 1995; 268 (1 Pt 2): 92–7Google Scholar
  15. 15.
    Vogt M, Puntschart A, Geiser J, et al. Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions. J Appl Physiol 2001; 91 (1): 173–82PubMedGoogle Scholar
  16. 16.
    Febbraio MA, Koukoulas I. HSP72 gene expression progres sively increases in human skeletal muscle during prolonged exhaustive exercise. J Appl Physiol 2000; 89 (3): 1055–60PubMedGoogle Scholar
  17. 17.
    Liu Y, Mayr S, Opitz-Gress A, et al. Human skeletal muscle HSP70 response to training in highly trained rowers. J Appl Physiol 1999; 86 (1): 101–4PubMedGoogle Scholar
  18. 18.
    Fehrenbach E, Passek F, Niess AM, et al. HSP expression in human leukocytes is modulated by endurance exercise. Med Sci Sports Exerc 2000; 32 (3): 592–600PubMedCrossRefGoogle Scholar
  19. 19.
    Fehrenbach E, Niess AM, Veith R, et al. Changes of HSP72 expression in leukocytes are associated with adaptation to exercise under conditions of high environmental temperature. JLeukoc Biol 2001; 69 (5): 747–54Google Scholar
  20. 20.
    Fehrenbach E, Veith R, Schmid M, et al. Inverse response of leukocyte heat shock proteins and DNA damage to exercise and heat. Free Radic Res 2003; 37 (9): 975–82PubMedCrossRefGoogle Scholar
  21. 21.
    Donati YR, Slosman DO, Polla BS. Oxidative injury and the heat shock response. Biochem Pharmacol 1990; 40 (12): 2571–7PubMedCrossRefGoogle Scholar
  22. 22.
    Blake MJ, Udelsman R, Feulner GJ, et al. Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response. Proc Natl Acad Sci USA 1991; 88 (21): 9873–7PubMedCrossRefGoogle Scholar
  23. 23.
    Febbraio MA, Mesa JL, Chung J, et al. Glucose ingestion attenuates the exercise-induced increase in circulating heat shock protein 72 and heat shock protein 60 in humans. Cell Stress Chaperones 2004; 9 (4): 390PubMedCrossRefGoogle Scholar
  24. 24.
    Maloyan A, Horowitz M. Beta-adrenergic signaling and thyroid hormones affect HSP72 expression during heat acclimation. J Appl Physiol 2002; 93 (1): 107–15PubMedGoogle Scholar
  25. 25.
    Kregel KC. Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol 2002; 92 (5): 2177–86PubMedGoogle Scholar
  26. 26.
    Moseley PL. Heat shock proteins and heat adaptation of the whole organism. J Appl Physiol 1997; 83 (5): 1413–7PubMedGoogle Scholar
  27. 27.
    Malhotra V, Wong HR. Interactions between the heat shock response and the nuclear factor-kappaB signaling pathway. Crit Care Med 2002; 30 (1 Suppl.): 89–95CrossRefGoogle Scholar
  28. 28.
    Ryan AJ, Flanagan SW, Moseley PL, et al. Acute heat stress protects rats against endotoxin shock. J Appl Physiol 1992; 73 (4): 1517–22PubMedGoogle Scholar
  29. 29.
    Lancaster GI, Moller K, Nielsen B, et al. Exercise induces the release of heat shock protein 72 from the human brain in vivo. Cell Stress Chaperones 2004; 9 (3): 276–80PubMedCrossRefGoogle Scholar
  30. 30.
    Guzhova I, Kislyakova K, Moskaliova O, et al. In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 2001; 914 (1-2): 66–73PubMedCrossRefGoogle Scholar
  31. 31.
    Clayton A, Turkes A, Navabi H, et al. Induction of heat shock proteins in B-cell exosomes. J Cell Sci 2005; 118 (Pt 16): 3631–8PubMedCrossRefGoogle Scholar
  32. 32.
    Lancaster GI, Febbraio MA. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 2005; 280 (24): 23349–55PubMedCrossRefGoogle Scholar
  33. 33.
    Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endog enous activators of dendritic cells. Nat Med 1999; 5 (11):1249–55PubMedCrossRefGoogle Scholar
  34. 34.
    Broquet AH, Thomas G, Masliah J, et al. Expression of the molecular chaperone Hsp 70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 2003; 24 (13): 21601–6CrossRefGoogle Scholar
  35. 35.
    Radons J, Multhoff G. Immunostimulatory functions of membrane-bound and exported heat shock protein 70. ExercImmunol Rev 2005; 11: 17–33PubMedGoogle Scholar
  36. 36.
    Multhoff G, Botzler C, Jennen L, et al. Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 1997; 158 (9): 4341–50PubMedGoogle Scholar
  37. 37.
    Whitham M, Fortes M. Effect of blood handling on extracellular Hsp72 concentration after high-intensity exercise in humans. Cell Stress Chaperones 2006; 11 (4): 304–8PubMedCrossRefGoogle Scholar
  38. 38.
    Walsh RC, Koukoulas I, Garnham A, et al. Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 2001; 6 (4):386–93PubMedCrossRefGoogle Scholar
  39. 39.
    Shastry S, Toft DO, Joyner MJ. HSP70 and HSP90 expression in leucocytes after exercise in moderately trained humans. Acta Physiol Scand 2002; 175 (2): 139–46PubMedCrossRefGoogle Scholar
  40. 40.
    Ryan AJ, Gisolfi CV, Moseley PL. Synthesis of 70K stress protein by human leukocytes: effect of exercise in the heat. J Appl Physiol 1991; 70 (1): 466–71PubMedGoogle Scholar
  41. 41.
    Whitham M, Halson SL, Lancaster GI, et al. Leukocyte heat shock protein expression before and after intensified training. Int J Sports Med 2004; 25 (7): 522–7PubMedCrossRefGoogle Scholar
  42. 42.
    Lyashko VN, Vikulova VK, Chernicov VG, et al. Comparison of the heat shock response in ethnically and ecologically different human populations. Proc Natl Acad Sci USA 1994; 91 (26): p12492–5CrossRefGoogle Scholar
  43. 43.
    Sherwood SW, Rush D, Ellsworth JL, et al. Defining cellular senescence in IMR-90 cells: a flow cytometric analysis. Proc Natl Acad Sci USA 1988; 85 (23): 9086–90PubMedCrossRefGoogle Scholar
  44. 44.
    Moseley PL, Wallen ES, McCafferty JD, et al. Heat stress regulates the human 70-kDa heat-shock gene through the 3’— untranslated region. Am J Physiol 1993; 264 (6 Pt 1): 533–7Google Scholar
  45. 45.
    DiDomenico BJ, Bugaisky GE, Lindquist S. The heat shock transcriptional levels. Cell 1982; 31 (3 Pt 2): 593–603CrossRefGoogle Scholar
  46. 46.
    Henics T, Nagy E, Oh HJ, et al. Mammalian Hsp70 and Hsp110 proteins bind to RNA motifs involved in mRNA stability. J Biol Chem 1999; 274 (24): 17318–24PubMedCrossRefGoogle Scholar
  47. 47.
    McClung JP, Hasday JD, He JR, et al. Exercise-heat acclimation in humans alters baseline levels and ex vivo heat inducibility of HSP72 and HSP90 in peripheral blood mononuclear cells. Am J Physiol Regul Integr Comp Physiol 2008; 294 (1): 185–9CrossRefGoogle Scholar
  48. 48.
    Yamada PM, Amorim FT, Moseley P, et al. Effect of heat acclimation on heat shock protein 72 and interleukin-10 in humans. J Appl Physiol 2007; 103: 1196–204PubMedCrossRefGoogle Scholar
  49. 49.
    Shin Y, Oh J, Sohn H, et al. Expression of exercise-induced HSP 70 in long-distance runner. J Therm Biology 2004; 29 (7-8): 769–74CrossRefGoogle Scholar
  50. 50.
    Fehrenbach E, Niess AM, Schlotz E, et al. Transcriptional and translational regulation of heat shock proteins in leukocytes of endurance runners. J Appl Physiol 2000; 89 (2): 704–10PubMedGoogle Scholar
  51. 51.
    Morton JP, MacLaren DPM, Cable NT, et al. Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging tread-mill exercise. J Appl Physiol 2006; 101 (1): 176–82PubMedCrossRefGoogle Scholar
  52. 52.
    Khassaf M, Child RB, McArdle A, et al. Time course of responses of human skeletal muscle to oxidative stress induced by nondamaging exercise. J Appl Physiol 2001; 90 (3): 1031–5PubMedGoogle Scholar
  53. 53.
    Puntschart A, Vogt M, Widmer HR, et al. Hsp70 expression in human skeletal muscle after exercise. Acta Physiol Scand 1996; 157 (4): 411–7PubMedCrossRefGoogle Scholar
  54. 54.
    Watkins AM, Cheek DJ, Harvey AE, et al. Heat acclimation and HSP 72 expression in exercising humans. Int J Sports Med 2008; 29: 269–76PubMedCrossRefGoogle Scholar
  55. 55.
    Niess AM, Hartmann A, Grunert-Fuchs M, et al. DNA damage after exhaustive treadmill running in trained and untrained men. Int J Sports Med 1996; 17 (6): 397–403PubMedCrossRefGoogle Scholar
  56. 56.
    Petersen R, Lindquist S. The Drosophila hsp70 message is rapidly degraded at normal temperatures and stabilized by heat shock. Gene 1988; 72 (1-2): 161–8PubMedCrossRefGoogle Scholar
  57. 57.
    Fehrenbach E, Niess AM, Passek F, et al. Influence of different types of exercise on the expression of haem oxygenase-1 in leukocytes. J Sports Sci 2003; 21 (5): 383–9PubMedCrossRefGoogle Scholar
  58. 58.
    Willoughby DS, Priest JW, Nelson M. Expression of the stress proteins, ubiquitin, heat shock protein 72, and myofibrillar protein content after 12 weeks of leg cycling in persons with spinal cord injury. Arch Phys Med Rehabil 2002; 83 (5):649–54PubMedCrossRefGoogle Scholar
  59. 59.
    Marshall HC, Ferguson RA, Nimmo MA. Human resting extracellular heat shock protein 72 concentration decreases during the initial adaptation to exercise in a hot, humid environment. Cell Stress Chaperones 2006; 11 (2): 129–34PubMedCrossRefGoogle Scholar
  60. 60.
    Fleshner M, Johnson JD. Endogenous extra-cellular heat shock protein 72: releasing signal(s) and function. Int J Hyperthermia 2005; 21 (5): 457–71PubMedCrossRefGoogle Scholar
  61. 61.
    Fehrenbach E, Niess AM, Voelker K, et al. Exercise intensity and duration affect blood soluble HSP72. Int J Sports Med 2005; 26 (7): 552–7PubMedCrossRefGoogle Scholar
  62. 62.
    Fleshner M, Campisi J, Amiri L, et al. Cat exposure induces both intra and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology 2004; 29 (9): 1142–52PubMedCrossRefGoogle Scholar
  63. 63.
    Johnson JD, Campisi J, Sharkey CM, et al. Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72. J Appl Physiol 2005; 99 (5): 1789–95PubMedCrossRefGoogle Scholar
  64. 64.
    Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12: 991–1045PubMedCrossRefGoogle Scholar
  65. 65.
    Asea A, Kraeft SK, Kurt-Jones EA, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 2000; 6 (4): 435–42PubMedCrossRefGoogle Scholar
  66. 66.
    Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like re ceptor (TLR) 2 and TLR4. J Biol Chem 2002; 277 (17):15028–34PubMedCrossRefGoogle Scholar
  67. 67.
    Vabulas RM, Ahmad-Nejad P, Ghose S, et al. HSP70 as endog enous stimulus of the Toll/interleukin-1 receptor signal path way. J Biol Chem 2002; 277 (17): 15107–12PubMedCrossRefGoogle Scholar
  68. 68.
    Visintin A, Mazzoni A, Spitzer JH, et al. Regulation of Toll like receptors in human monocytes and dendritic cells. J Immunol 2001; 166 (1): 249–55PubMedGoogle Scholar
  69. 69.
    Moseley PL. Exercise, stress, and the immune conversation. Exerc Sport Sci Rev 2000; 28 (3): 128–32PubMedGoogle Scholar
  70. 70.
    Thompson HS, Maynard EB, Morales ER, et al. Exercise induced HSP27, HSP70 and MAPK responses in human skeletal muscle. Acta Physiol Scand 2003; 178 (1): 61–72PubMedCrossRefGoogle Scholar
  71. 71.
    Oehler R, Pusch E, Zellner M, et al. Cell type-specific variations in the induction of hsp 70 in human leukocytes by feverlike whole body hyperthermia. Cell Stress Chaperones 2001; 6 (4): 306–15PubMedCrossRefGoogle Scholar
  72. 72.
    Nickerson M, Kennedy SL, Johnson JD, et al. Sexual dimorphism of the intracellular heat shock protein 72 response. J Appl Physiol 2006; 101: 566–75PubMedCrossRefGoogle Scholar
  73. 73.
    Paroo Z, Tiidus PM, Noble EG. Estrogen attenuates HSP 72 expression in acutely exercised male rodents.Eur J Appl Physiol Occup Physiol 1999; 80 (3): 180–4PubMedCrossRefGoogle Scholar
  74. 74.
    Paroo Z, Dipchand ES, Noble EG. Estrogen attenuates postexercise HSP70 expression in skeletal muscle. Am J Physiol Cell Physiol 2002; 282 (2): 245–51Google Scholar
  75. 75.
    Ayres S, Abplanalp W, Liu JH, et al. Mechanisms involved in the protective effect of estradiol-17beta on lipid peroxidation and DNA damage. Am J Physiol 1998; 274 (6 Pt 1): 1002–8Google Scholar
  76. 76.
    Wiseman H, Quinn P. The antioxidant action of synthetic oestrogens involves decreased membrane fluidity: relevance to their potential use as anticancer and cardioprotective agents compared to tamoxifen? Free Radic Res 1994; 21 (3): 187–94PubMedCrossRefGoogle Scholar
  77. 77.
    Caulin-Glaser T, Watson CA, Pardi R, et al. Effects of 17beta estradiol on cytokine-induced endothelial cell adhesion mole cule expression. J Clin Invest 1996; 98 (1): 36–42PubMedCrossRefGoogle Scholar
  78. 78.
    Yoshikawa T, Yoshida N. Vitamin E and leukocyte-endothelial cell interactions. Antioxid Redox Signal 2000; 2 (4): 821–5PubMedCrossRefGoogle Scholar
  79. 79.
    Hamilton KL, Gupta S, Knowlton AA. Estrogen and regulation of heat shock protein expression in female cardiomyocytes: cross-talk with NF kappa B signaling. J Mol Cell Cardiol 2004;36 (4): 577–84PubMedCrossRefGoogle Scholar
  80. 80.
    Khassaf M, McArdle A, Esanu C, et al. Effect of vitamin C supplements on antioxidant defence and stress proteins in human lymphocytes and skeletal muscle. J Physiol 2003; 549 (2): 645–52PubMedCrossRefGoogle Scholar
  81. 81.
    Fischer CP, Hiscock NJ, Basu S, et al. Vitamin E isoform specific inhibition of the exercise-induced heat shock protein 72 expression in humans. J Appl Physiol 2006; 100: 1679–87PubMedCrossRefGoogle Scholar
  82. 82.
    Rao DV, Watson K, Jones GL. Age-related attenuation in the expression of the major heat shock proteins in human peripheral lymphocytes. Mech Ageing Dev 1999; 107 (1): 105–18PubMedCrossRefGoogle Scholar
  83. 83.
    Deguchi Y, Negoro S, Kishimoto S. Age-related changes of heat shock protein gene transcription in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 1988; 157 (2): 580–4PubMedCrossRefGoogle Scholar
  84. 84.
    Luce MC, Cristofalo VJ. Reduction in heat shock gene expression correlates with increased thermosensitivity in senescent human fibroblasts. Exp Cell Res 1992; 202 (1): 9–16PubMedCrossRefGoogle Scholar
  85. 85.
    Jurivich DA, Qiu L, Welk JF. Attenuated stress responses in young and old human lymphocytes. Mech Ageing Dev 1997; 94 (1-3): 233–49PubMedCrossRefGoogle Scholar
  86. 86.
    Liu AY, Lin Z, Choi HS, et al. Attenuated induction of heat shock gene expression in aging diploid fibroblasts. J Biol Chem 1989; 264 (20): 12037–45PubMedGoogle Scholar
  87. 87.
    Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 1993; 90 (17): 7915–22PubMedCrossRefGoogle Scholar
  88. 88.
    Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000; 408 (6809): 239–47PubMedCrossRefGoogle Scholar
  89. 89.
    Kregel KC, Moseley PL. Differential effects of exercise and heat stress on liver HSP70 accumulation with aging. J Appl Physiol 1996; 80 (2): 547–51PubMedGoogle Scholar
  90. 90.
    Ruell PA, Thompson MW, Hoffman KM, et al. Plasma Hsp72 is higher in runners with more serious symptoms of exertional heat illness. Eur J Appl Physiol 2006; 97 (6): 732–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV. 2008

Authors and Affiliations

  • Paulette Yamada
    • 1
  • Fabiano Amorim
    • 1
  • Pope Moseley
    • 2
  • Suzanne Schneider
    • 1
  1. 1.Department of Health, Exercise and Sports SciencesUniversity of New MexicoAlbuquerqueUSA
  2. 2.Department of Internal MedicineUniversity of New Mexico School of MedicineAlbuquerqueUSA

Personalised recommendations