Gilliam 2013 Free Radic Biol Med

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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.

» PMID: 24017970 Open Access

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 (ΔΨ(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.

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

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