Mitochondria-derived superoxide links to tourniquet-induced apoptosis in mouse skeletal muscle.
Our previous study has reported that superoxide mediates ischemia-reperfusion (IR)-induced necrosis in mouse skeletal muscle. However, it remains poorly understood whether IR induces apoptosis and what factors are involved in IR-induced apoptosis in skeletal muscle. Using a murine model of tourniquet-induced hindlimb IR, we investigated the relationship between mitochondrial dysfunction and apoptosis in skeletal muscle. Hindlimbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Compared to sham treatment, tourniquet-induced IR significantly elevated mitochondria-derived superoxide production, activated opening of mitochondrial permeability transition pore (mPTP), and caused apoptosis in the gastrocnemius muscles. Pretreatment with a superoxide dismutase mimetic (tempol, 50 mg/kg) or a mitochondrial antioxidant (co-enzyme Q(10), 50 mg/kg) not only decreased mitochondria-derived superoxide production, but also inhibited mPTP opening and apoptosis in the IR gastrocnemius muscles. Additionally, an inhibitor of mPTP (cyclosporine A, 50 mg/kg) also inhibited both mPTP opening and apoptosis in the IR gastrocnemius muscles. These results suggest that mitochondria-derived superoxide overproduction triggers the mPTP opening and subsequently causes apoptosis in tourniquet-induced hindlimb IR.
Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States.
Thai P
TP
Tran
Huiyin
H
Tu
Jinxu
J
Liu
Robert L
RL
Muelleman
Yu-Long
YL
Li
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology*; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism*; D014111:Tourniquets / Q000009:adverse effects*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
D000975:Antioxidants; D003497:Cyclic N-Oxides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013113:Spin Labels; D014815:Vitamins; D013481:Superoxides; D014451:Ubiquinone; D016572:Cyclosporine; D003576:Electron Transport Complex IV; D053453:Caspase 9; C024989:coenzyme Q10; C001803:tempol