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 (20 mg/kg). Initially at 2 h doxorubicin inhibits both Complex I- and II-supported respiration and increases H2O2 emission, both of which are partially restored after 24 h. The relationship between oxygen consumption and membrane potential (ΞΞ¨(mt)) is shifted to the right at 24 h, indicating elevated reducing pressure within the electron transfer-pathway (ET-pathway). Respiratory capacity is further decreased at a later time point (72 h) along with H2O2-emitting potential and an increased sensitivity to mitochondrial permeability transition pore (mtPTP) opening. These novel findings suggest a role for skeletal muscle mitochondria as a potential underlying cause of doxorubicin-induced muscle dysfunction. β’ Keywords: Chemotherapy, ET-pathway, 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, ET
Pathway: N, S
HRR: Oxygraph-2k, TPP