TY - JOUR
T1 - Tourniquet-induced acute ischemia-reperfusion injury in mouse skeletal muscles
T2 - Involvement of superoxide
AU - Tran, Thai P.
AU - Tu, Huiyin
AU - Pipinos, Iraklis I.
AU - Muelleman, Robert L.
AU - Albadawi, Hassan
AU - Li, Yu Long
N1 - Funding Information:
The authors wish to thank Michael T. Watkins, MD, Department of Surgery, Division of Vascular Surgery, Massachusetts General Hospital, Harvard Medical for his generous help with model development; Zhen Zhu, MD, Ilir Frokkaj, MD, Stanley Swanson, BS, Tanuja Lakshmi, MD, and George P. Casale, PhD, Department of Surgery, University of Nebraska Medical Center for their skilled technical support. This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-098503 to Y.L. Li.
PY - 2011/1/10
Y1 - 2011/1/10
N2 - Although arterial limb tourniquet is one of the first-line treatments to prevent exsanguinating hemorrhage in both civilian pre-hospital and battlefield casualty care, prolonged application of a limb tourniquet can lead to serious ischemia-reperfusion injury. However, the underlying pathomechanisms of tourniquet-induced ischemia-reperfusion injury are still poorly understood. Using a murine model of acute limb ischemia-reperfusion, we investigated if acute limb ischemia-reperfusion injury is mediated by superoxide overproduction and mitochondrial dysfunction. Hind limbs 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. Approximately 40% of the gastrocnemius muscle suffered infarction in this model. Activities of mitochondrial electron transport chain complexes including complex I, II, III, and IV in the gastrocnemius muscle were decreased in the ischemia-reperfusion group compared to sham. Superoxide production was increased while activity of manganese superoxide dismutase (MnSOD, the mitochondria-targeted SOD isoform) was decreased in the ischemia-reperfusion group compared to the sham group. Pretreatment with tempol (a SOD mimetic, 50 mg/kg) or co-enzyme Q10 (50 mg/kg) not only decreased the superoxide production, but also reduced the infarct size and normalized mitochondrial dysfunction in the gastrocnemius muscle. Our results suggest that tourniquet-induced skeletal muscle ischemia-reperfusion injuries including infarct size and mitochondrial dysfunction may be mediated via superoxide overproduction and reduced antioxidant activity. In the future, this murine ischemia-reperfusion model can be adapted to mechanistically evaluate anti-ischemic molecules in tourniquet-induced skeletal muscle injury.
AB - Although arterial limb tourniquet is one of the first-line treatments to prevent exsanguinating hemorrhage in both civilian pre-hospital and battlefield casualty care, prolonged application of a limb tourniquet can lead to serious ischemia-reperfusion injury. However, the underlying pathomechanisms of tourniquet-induced ischemia-reperfusion injury are still poorly understood. Using a murine model of acute limb ischemia-reperfusion, we investigated if acute limb ischemia-reperfusion injury is mediated by superoxide overproduction and mitochondrial dysfunction. Hind limbs 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. Approximately 40% of the gastrocnemius muscle suffered infarction in this model. Activities of mitochondrial electron transport chain complexes including complex I, II, III, and IV in the gastrocnemius muscle were decreased in the ischemia-reperfusion group compared to sham. Superoxide production was increased while activity of manganese superoxide dismutase (MnSOD, the mitochondria-targeted SOD isoform) was decreased in the ischemia-reperfusion group compared to the sham group. Pretreatment with tempol (a SOD mimetic, 50 mg/kg) or co-enzyme Q10 (50 mg/kg) not only decreased the superoxide production, but also reduced the infarct size and normalized mitochondrial dysfunction in the gastrocnemius muscle. Our results suggest that tourniquet-induced skeletal muscle ischemia-reperfusion injuries including infarct size and mitochondrial dysfunction may be mediated via superoxide overproduction and reduced antioxidant activity. In the future, this murine ischemia-reperfusion model can be adapted to mechanistically evaluate anti-ischemic molecules in tourniquet-induced skeletal muscle injury.
KW - Infarct size
KW - Ischemia-reperfusion injury
KW - Mitochondria
KW - Superoxide
KW - Tourniquet
UR - http://www.scopus.com/inward/record.url?scp=78649730399&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78649730399&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2010.10.037
DO - 10.1016/j.ejphar.2010.10.037
M3 - Article
C2 - 21036124
AN - SCOPUS:78649730399
SN - 0014-2999
VL - 650
SP - 328
EP - 334
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -