Cell Stress and Chaperones

, Volume 21, Issue 6, pp 1111–1117 | Cite as

Utility of 17-(allylamino)-17-demethoxygeldanamycin treatment for skeletal muscle injury

  • Cory W. BaumannEmail author
  • Russell G. Rogers
  • Jeffrey S. Otis
Short Communication


Repeated eccentric contractions can injure skeletal muscle and result in functional deficits that take several weeks to fully recover. The 70-kDa heat shock protein (Hsp70) is a stress-inducible molecular chaperone that maintains protein quality and plays an integral role in the muscle’s repair processes following injury. Here, we attempted to hasten this recovery by pharmacologically inducing Hsp70 expression in mouse skeletal muscle with 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (40 mg/kg) both prior to and throughout the first 7 days after an injurious bout of 150 maximal eccentric contractions. Hsp70 content in the injured skeletal muscle was strongly induced following the eccentric contractions and remained elevated over the next 7 days as the muscle underwent repair. Treatment with 17-AAG increased Hsp70 content ∼fivefold; however, this was significantly less than that induced by the injury. Moreover, 17-AAG treatment did not recover the decrements to in vivo isometric torque production following the bout of eccentric contractions. Together, these findings demonstrate that although Hsp70 content was induced in the uninjured skeletal muscle, treatment of 17-AAG (40 mg/kg) was not a preventive measure to either reduce the severity of skeletal muscle damage or enhance functional recovery following a bout of maximal eccentric contractions.


Chaperones Damage Eccentric contractions Isometric torque Mouse model 


Compliance with ethical standards

All procedures were approved by the Georgia State University Institutional Animal Care and Use Committee.


This study was partially supported by a NIA/NIH training grant (T32-AG029796).


No conflicts of interest, financial or otherwise, are declared by the authors.


  1. Baumann CW, Otis JS (2015) 17-(allylamino)-17-demethoxygeldanamycin drives Hsp70 expression but fails to improve morphological or functional recovery in injured skeletal muscle. Clin Exp Pharmacol Physiol 42:1308–1316CrossRefPubMedGoogle Scholar
  2. Baumann CW, Rogers RG, Gahlot N, Ingalls CP (2014a) Eccentric contractions disrupt FKBP12 content in mouse skeletal muscle. Physiol Rep 2:e12081. doi: 10.14814/phy2.12081 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Baumann CW, Rogers RG, Lees SJ, Otis JS (2014b) Muscular strength is unaffected by short-term resveratrol supplementation in aged mouse muscle. Int J Clin Exp Physiol 1:253–257CrossRefGoogle Scholar
  4. Baumann CW, Rogers RG, Otis JS, Ingalls CP (2016) Recovery of strength is dependent on mTORC1 signaling after eccentric muscle injury. Muscle NerveGoogle Scholar
  5. Corona BT, Balog EM, Doyle JA, Rupp JC, Luke RC, Ingalls CP (2010) Junctophilin damage contributes to early strength deficits and EC coupling failure after eccentric contractions. Am J Phys Cell Phys 298:C365–C376CrossRefGoogle Scholar
  6. Edwards R, Hill D, Jones D, Merton P (1977) Fatigue of long duration in human skeletal muscle after exercise. J Physiol 272:769–778CrossRefPubMedPubMedCentralGoogle Scholar
  7. Egorin MJ, Zuhowski EG, Rosen DM, Sentz DL, Covey JM, Eiseman JL (2001) Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) in CD2F1 mice1. Cancer Chemother Pharmacol 47:291–302CrossRefPubMedGoogle Scholar
  8. Holwerda AM, Locke M (2014) Hsp25 and Hsp72 content in rat skeletal muscle following controlled shortening and lengthening contractions. Appl Physiol Nutr Metab 39:1380–1387CrossRefPubMedGoogle Scholar
  9. Ingalls C, Warren G, Armstrong R (1998a) Dissociation of force production from MHC and actin contents in muscles injured by eccentric contractions. J Muscle Res Cell Motil 19:215–224CrossRefPubMedGoogle Scholar
  10. Ingalls C, Warren G, Williams J, Ward C, Armstrong R (1998b) E-C coupling failure in mouse EDL muscle after in vivo eccentric contractions. J Appl Physiol 85:58–67PubMedGoogle Scholar
  11. Ingalls CP, Wenke JC, Nofal T, Armstrong RB (2004) Adaptation to lengthening contraction-induced injury in mouse muscle. J Appl Physiol 97:1067–1076CrossRefPubMedGoogle Scholar
  12. Jones DA, Howell S, Roussos C, Edwards RH (1982) Low-frequency fatigue in isolated skeletal muscles and the effects of methylxanthines. Clin Sci (Lond) 63:161–167CrossRefGoogle Scholar
  13. Kayani AC, Close GL, Broome CS, Jackson MJ, McArdle A (2008a) Enhanced recovery from contraction-induced damage in skeletal muscles of old mice following treatment with the heat shock protein inducer 17-(allylamino)-17-demethoxygeldanamycin. Rejuvenation Res 11:1021–1030CrossRefPubMedGoogle Scholar
  14. Kayani AC, Close GL, Jackson MJ, McArdle A (2008b) Prolonged treadmill training increases HSP70 in skeletal muscle but does not affect age-related functional deficits. Am J Phys Regul Integr Comp Phys 294:R568–R576Google Scholar
  15. Kiang JG, Tsokos GC (1998) Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther 80:183–201CrossRefPubMedGoogle Scholar
  16. Lewis EJ, Ramsook AH, Locke M, Amara CE (2013) Mild eccentric exercise increases Hsp72 content in skeletal muscles from adult and late middle-aged rats. Cell Stress Chaperones 18:667–673CrossRefPubMedPubMedCentralGoogle Scholar
  17. Liu Y, Gampert L, Nething K, Steinacker JM (2006) Response and function of skeletal muscle heat shock protein 70. Front Biosci 11:2802–2827CrossRefPubMedGoogle Scholar
  18. Lomonosova YN, Shenkman BS, Nemirovskaya TL (2012) Attenuation of unloading-induced rat soleus atrophy with the heat-shock protein inducer 17-(allylamino)-17-demethoxygeldanamycin. FASEB J 26:4295–4301CrossRefPubMedGoogle Scholar
  19. Lowe DA, Warren GL, Ingalls CP, Boorstein DB, Armstrong R (1995) Muscle function and protein metabolism after initiation of eccentric contraction-induced injury. J Appl Physiol 79:1260–1270PubMedGoogle Scholar
  20. Marques C, Guo W, Pereira P, Taylor A, Patterson C, Evans PC, Shang F (2006) The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. FASEB J 20:741–743PubMedPubMedCentralGoogle Scholar
  21. Mayer M, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684CrossRefPubMedPubMedCentralGoogle Scholar
  22. McArdle A, Dillmann WH, Mestril R, Faulkner JA, Jackson MJ (2004) Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age-related muscle dysfunction. FASEB J 18:355–357PubMedGoogle Scholar
  23. Morimoto R (1991) Heat shock: the role of transient inducible responses in cell damage, transformation, and differentiation. Cancer Cells (Cold Spring Harbor, NY: 1989) 3:295–301Google Scholar
  24. Page J, Heath J, Fulton R, Yalkowsky E, Tabibi E, Tomaszewski J, Smith A, Rodman L Comparison of geldanamycin (NSC-122750) and 17-allylaminogeldanamycin (NSC-330507D) toxicity in rats [abstract]. In: Proc Am Assoc Cancer Res Annu Meet, 1997. p 308Google Scholar
  25. Paulsen G, Vissing K, Kalhovde JM, Ugelstad I, Bayer ML, Kadi F, Schjerling P, Hallén J, Raastad T (2007) Maximal eccentric exercise induces a rapid accumulation of small heat shock proteins on myofibrils and a delayed HSP70 response in humans. Am J Phys Regul Integr Comp Phys 293:R844–R853Google Scholar
  26. Rathbone CR, Wenke J, Warren GL, Armstrong R (2003) Importance of satellite cells in the strength recovery after eccentric contraction-induced muscle injury. Am J Phys Regul Integr Comp Phys 285:R1490–R1495Google Scholar
  27. Rogers RG, Baumann CW, Otis JS (2015) Recovery of skeletal muscle function following injury is not augmented by acute resveratrol supplementation. Int J Clin Exp Physiol 2:29–33CrossRefGoogle Scholar
  28. Senf SM (2013) Skeletal muscle heat shock protein 70: diverse functions and therapeutic potential for wasting disorders. Front Physiol 4Google Scholar
  29. Solit DB, Zheng FF, Drobnjak M, Münster PN, Higgins B, Verbel D, Heller G, Tong W, Cordon-Cardo C, Agus DB (2002) 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 8:986–993PubMedGoogle Scholar
  30. Sõti C, Nagy E, Giricz Z, Vígh L, Csermely P, Ferdinandy P (2005) Heat shock proteins as emerging therapeutic targets. Br J Pharmacol 146:769–780CrossRefPubMedPubMedCentralGoogle Scholar
  31. Thompson H, Scordilis S, Clarkson P, Lohrer W (2001) A single bout of eccentric exercise increases HSP27 and HSC/HSP70 in human skeletal muscle. Acta Physiol Scand 171:187–193CrossRefPubMedGoogle Scholar
  32. Touchberry CD, Gupte AA, Bomhoff GL, Graham ZA, Geiger PC, Gallagher PM (2012) Acute heat stress prior to downhill running may enhance skeletal muscle remodeling. Cell Stress Chaperones 17:693–705CrossRefPubMedPubMedCentralGoogle Scholar
  33. Vasilaki A, Jackson MJ, McArdle A (2002) Attenuated HSP70 response in skeletal muscle of aged rats following contractile activity. Muscle Nerve 25:902–905CrossRefPubMedGoogle Scholar
  34. Wagatsuma A, Shiozuka M, Kotake N, Takayuki K, Yusuke H, Mabuchi K, Matsuda R, Yamada S (2011) Pharmacological inhibition of HSP90 activity negatively modulates myogenic differentiation and cell survival in C2C12 cells. Mol Cell Biochem 358:265–280CrossRefPubMedGoogle Scholar
  35. Warren GL, Lowe DA, Armstrong RB (1999) Measurement tools used in the study of eccentric contraction-induced injury. Sports Med 27:43–59CrossRefPubMedGoogle Scholar
  36. Warren GL, Ingalls CP, Lowe DA, Armstrong R (2001) Excitation-contraction uncoupling: major role in contraction-induced muscle injury. Exerc Sport Sci Rev 29:82–87CrossRefPubMedGoogle Scholar
  37. Warren GL, Hulderman T, Jensen N, McKinstry M, Mishra M, Luster MI, Simeonova PP (2002) Physiological role of tumor necrosis factor α in traumatic muscle injury. FASEB J 16:1630–1632PubMedGoogle Scholar

Copyright information

© Cell Stress Society International 2016

Authors and Affiliations

  • Cory W. Baumann
    • 1
    Email author
  • Russell G. Rogers
    • 2
  • Jeffrey S. Otis
    • 2
  1. 1.Department of Physical Medicine and RehabilitationUniversity of Minnesota Medical SchoolMinneapolisUSA
  2. 2.Department of Kinesiology and HealthGeorgia State UniversityAtlantaUSA

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