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Free Radic Biol Med. 2013 Dec;65:988-996. doi: 10.1016/j.freeradbiomed.2013.08.191. Epub 2013 Sep 7.

The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle.

Author information

1
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.
2
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA.
3
East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA; Department of Physiology, East Carolina University, Greenville, NC 27858, USA.
4
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.

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.

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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