Mitochondrial ABCB7 Is Required For Exercise-induced Protection Against Doxorubicin Respiratory Muscle Toxicity

PURPOSE: Doxorubicin (DOX) is a potent anticancer drug; however, its side effects include dyspnea, reduced respiratory capacity, and exercise intolerance. While there is no clinical remedy to combat these adverse effects, our prior work indicates that endurance exercise preconditioning may safeguard respiratory (i.e. diaphragm) muscle function in DOX-treated animals by increasing the expression of mitochondria-localized ATP-binding cassette subfamily B member 7 (ABCB7). Therefore, we examined whether ABCB7 is required for exercise preconditioning-induced protection against DOX respiratory muscle toxicity. This was assessed by inhibiting the exercise-induced increase in ABCB7 expression using a targeted antisense oligonucleotide (ASO7). METHOD: Female Sprague-Dawley rats were either sedentary (SED) or underwent a 2-week treadmill preconditioning regimen (5 days/week, 60 min/day, 30 m/min, 0% grade) (EX). Immediately following each exercise session, the rats received either ASO7 (10 mg/kg IP) or saline (SAL). Twenty-four hours after the final exercise bout, rats were treated with either a bolus dose of DOX (20 mg/kg IP) or SAL. Endpoint measurements were made, and tissue was collected 48 hours afterward. Data were compared by two-way analysis of variance to determine the effects of drug treatment and activity. RESULTS: Our data demonstrated significant weight loss in all DOX-treated groups compared with the EX-SAL-SAL group from pre- to post- DOX/SAL treatment (EX-SAL-SAL = +12.95 ± 3.62 g, SED-SAL-DOX = -4.00 ± 1.13 g, EX-SAL-DOX = -0.20 ± 1.98 g, EX-ASO7-DOX = -4.80 ± 2.30 g, p < 0.05). Exercise capacity showed a reduced run time to fatigue in the SED-SAL-DOX group compared to exercise preconditioned DOX-treated rats (SED-SAL-DOX = 39.10 ± 1.85 min, EX-SAL-DOX = 56.99 ± 3.14 min, EX-ASO7-DOX = 55.18 ± 2.83 min, p < 0.05). Importantly, exercise preconditioning preserved diaphragm specific force production in EX-SAL-DOX rats compared to SED-SAL-DOX and EX-ASO7-DOX at frequencies of 30 Hz and greater (max force; EX-SAL-DOX = 21.97 ± 0.94 N/cm2, SED-SAL-DOX 18.60 ± 0.62 N/cm2, EX-ASO7-DOX = 17.79 ± 0.96 N/cm2, p < 0.05). CONCLUSION: These data establish a role for ABCB7 expression in the exercise preconditioning-induced protection against DOX respiratory muscle dysfunction. NHLBI R01 HL146443