Functional Deficits Are Not Attenuated by Increasing Hsp70 Content Prior to Trauma-induced Injury

Abstract

PURPOSE: Trauma-induced skeletal muscle injury results in functional deficits that can take several weeks to fully recover. Ultimate recovery of function is dependent on the muscle’s ability to regenerate, a highly coordinated process that involves transient muscle inflammation, removal of necrotic cellular debris and subsequent replacement of damaged myofibers. Instrumental in these events is the70 kDa heat shock protein (Hsp70), a critical chaperone protein that increases in content shortly after stress. By manipulating Hsp70 content prior to injury, many proteins and genes involved in regeneration can be altered; however, what is less apparent is how these alterations affect function. Therefore, the aim of this study was to determine if pharmacological induction of Hsp70 in muscle of young mice would enhance recovery from trauma-induced damage. METHODS: Skeletal muscle injury was induced through an intramuscular injection of 50 μl of a 1.2% BaCl2 solution to the tibialis anterior (TA) muscle. Three days prior to and weekly for 21 days post-injury mice were treated with 40 mg/kg of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) or a vehicle (DMSO). To assess if 17AAG treatment attenuated functional deficit, in vivo peak isometric torque of the anterior crural muscles was measured immediately before and 7 or 14 days into recovery, and the TA muscles were excised for biochemical and histological analysis. RESULTS: Following the BaCl2 injection in the vehicle-treated mice, cross-sectional area of the regenerating fibers was decreased 7 (~45%) and 14 (~20%) days post-injury, which paralleled reductions in peak isometric torque [7 (~75%) and 14 (~30%) days]. Treatment of 17AAG significantly increased Hsp70 muscle content before the injury but had no effect on torque deficits or cross-sectional area when compared to the vehicle-treated mice. CONCLUSIONS: These data suggest that 17AAG was affective at increasing Hsp70 content prior to the injury, however due to the overwhelming amount of damage and necrosis following the BaCl2 injection, 17AAG was unable to attenuate functional and histological deficits 7 and 14 days into recovery.