title: The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.
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 (ΔΨ) 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 (72 h) 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.
authors.affiliation: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Physiology, East Carolina University, Greenville, NC 27858, USA. Electronic address: gilliaml@ecu.edu.
authors.forename: Laura A A
authors.initials: LAA
authors.lastname: Gilliam
authors.affiliation: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA.
authors.forename: Kelsey H
authors.initials: KH
authors.lastname: Fisher-Wellman
authors.affiliation: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Physiology, East Carolina University, Greenville, NC 27858, USA.
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lin
authors.affiliation: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Maples
authors.affiliation: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Physiology, East Carolina University, Greenville, NC 27858, USA.
authors.forename: Brook L
authors.initials: BL
authors.lastname: Cathey
authors.affiliation: East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Physiology, East Carolina University, Greenville, NC 27858, USA; Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA.
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D017207:Rats, Sprague-Dawley
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D006861:Hydrogen Peroxide
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
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