Potential biomarkers and preventative interventions for muscle wasting in adolescent and young adults with cancer: A translational study

Adolescent and young adults (AYAs) with sarcoma and our mouse model were used to evaluate early and late effects of doxorubicin (Dox) on skeletal muscle and the impact of physical activity on preventing Dox-induced damage. Skeletal muscle changes in 46 AYAs were quantified using computed tomography scans pre- and post- high-dose Dox treatment. Physical activity was monitored via wearable device. Patient blood samples were analyzed for myo-miRNA changes. In mice, we analyzed acute and late effects of Dox vs. Dox + exercise on skeletal muscle histology, Z-disc morphology, collagen deposition, changes in IL-6 and myo-miRNA, and changes in blood flow. During chemotherapy, AYA patients had poor physical activity levels and experienced an average muscle area and density reduction of -13.2% ± 10.9% (p < 0.01) and − 10.9% ± 25.6% (p = 0.01), respectively. In mice, there was an increase in number of abnormal mitochondria, autophagosomes, and disruption in Z-discs in the hindlimb at both 2 and 12-weeks post Dox. In patients and mice, miR-133b, miR-206, and miR-126 significantly decreased after Dox exposure. In the mouse model, exercise prevented all Dox-induced morphologic changes and acute Dox-induced decrease in muscle blood flow. Dox therapy resulted in skeletal muscle loss and reduction in muscle-specific miRNAs (miR-133b, 206, and 126) in plasma from mice and AYA patients, as well as in mouse muscle tissue. Changes in muscle morphology were not seen in mice that exercised, thus indicating the potential use of exercise as an intervention to prevent Dox-induced muscle damage.