Doxorubicin impairs skeletal muscle mitochondrial respiratory capacity in skeletal muscle

Debilitating muscle weakness and fatigue are common side effects of chemotherapy in cancer patients, limiting recovery and increasing morbidity. Our previous work shows that doxorubicin, a common chemotherapy drug, elevates reactive oxygen species (ROS) and decreases contractile force in skeletal muscle. As mitochondria represent a primary source of oxidant generation in muscle, we hypothesized that doxorubicin may compromise mitochondrial respiratory control and increase ROS production. 72 hrs following a single doxorubicin injection (20 mg/kg), maximal ADP‐stimulated O 2 consumption was decreased during respiration supported by palmitoylcarnitine (PC) (−46 ± 26 %, p<0.05) and pyruvate/malate (−43 ± 21 %, p<0.05, n=6/group) in permeabilized fiber bundles (PmFB) from red gastrocnemius muscle. PmFB from doxorubicin treated animals also display increased rates of mitochondrial H 2 O 2 emission with PC (23 ± 2 %) and 3‐phosphoglycerate (49 ± 2 %, p=0.1). Our data indicate that doxorubicin impairs both maximal State 3, and fatty‐acid‐supported respiration. In addition, doxorubicin promotes mitochondrial ROS generation, a potential underlying cause of doxorubicin‐induced muscle dysfunction. Supported by DK073488