Gilliam 2013 Free Radic Biol Med
Gilliam LA, Fisher-Wellman KH, Lin CT, Maples JM, Cathey BL, Neufer PD (2013) The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle. Free Radic Biol Med 65:988-96. |
Gilliam LA, Fisher-Wellman KH, Lin CT, Maples JM, Cathey BL, Neufer PD (2013) Free Radic Biol Med
Abstract: The combined loss of muscle strength and constant fatigue are disabling symptoms for cancer patients undergoing chemotherapy. Doxorubicin, a standard chemotherapy drug used in the clinic, causes skeletal muscle dysfunction and premature fatigue along with an increase in reactive oxygen species (ROS). As mitochondria represent a primary source of oxidant generation in muscle, we hypothesized that doxorubicin could negatively affect mitochondria by inhibiting respiratory capacity, leading to an increase in H2O2-emitting potential. Here we demonstrate a biphasic response of skeletal muscle mitochondria to a single doxorubicin injection (20mg/kg). Initially at 2h doxorubicin inhibits both complex I- and II-supported respiration and increases H2O2 emission, both of which are partially restored after 24h. The relationship between oxygen consumption and membrane potential (ΞΞ¨) is shifted to the right at 24h, indicating elevated reducing pressure within the electron transport system (ETS). Respiratory capacity is further decreased at a later time point (72h) along with H2O2-emitting potential and an increased sensitivity to mitochondrial permeability transition pore (mPTP) opening. These novel findings suggest a role for skeletal muscle mitochondria as a potential underlying cause of doxorubicin-induced muscle dysfunction. β’ Keywords: Chemotherapy, ETS, Metabolism, Mitochondria, PmFBs, ROS, Reactive oxygen species, Skeletal muscle, TPP, electron transport system, mPTP, mitochondrial permeability transition pore, permeabilized fiber bundles, reactive oxygen species, tetraphenylphosponium
β’ O2k-Network Lab: US NC Greenville Neufer PD
Labels: MiParea: Respiration, mt-Membrane, Pharmacology;toxicology
Pathology: Cancer
Stress:Permeability transition
Organism: Rat
Tissue;cell: Skeletal muscle
Preparation: Permeabilized tissue
Coupling state: OXPHOS, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property.
HRR: Oxygraph-2k, TPP