Mitochondria-derived superoxide links to tourniquet-induced apoptosis in mouse skeletal muscle

• Published in: PloS one Vol. 7; no. 8; p. e43410
• Main Authors: Tran, Thai P, Tu, Huiyin, Liu, Jinxu, Muelleman, Robert L, Li, Yu-Long
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.08.2012; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Antioxidants; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biology; Blotting, Western; Caspase 9 - metabolism; Cyclic N-Oxides - pharmacology; Cyclosporine - pharmacology; Cyclosporins; Electron Transport Complex IV - metabolism; Emergency medical care; Hindlimb - blood supply; Hindlimb - metabolism; Hindlimb - physiopathology; In Situ Nick-End Labeling; Inhibition; Ischemia; Kinases; Male; Medicine; Membrane permeability; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Mitochondrial DNA; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial Membrane Transport Proteins - physiology; Mitochondrial permeability transition pore; MPTP; Muscle, Skeletal - blood supply; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Muscles; Permeability; Pretreatment; Reperfusion; Reperfusion Injury - etiology; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Rodents; Rubber; Skeletal muscle; Spin Labels; Superoxide dismutase; Superoxides; Superoxides - metabolism; Tempol; Tourniquets - adverse effects; Trochanter; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; Vitamins - pharmacology; United States > US; Nebraska
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043410

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.