Utility of 17-(allylamino)-17-demethoxygeldanamycin treatment for skeletal muscle injury
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.
KeywordsChaperones 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.
- Baumann CW, Rogers RG, Otis JS, Ingalls CP (2016) Recovery of strength is dependent on mTORC1 signaling after eccentric muscle injury. Muscle NerveGoogle Scholar
- 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
- 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
- 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
- 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
- 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
- Senf SM (2013) Skeletal muscle heat shock protein 70: diverse functions and therapeutic potential for wasting disorders. Front Physiol 4Google Scholar
- 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