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Mitochondrial transplantation ameliorates acute limb ischemia

Arzoo Orfany, Carlos Galán Arriola, Ilias P. Doulamis, Alvise Guariento, Giovanna Ramirez-Barbieri, Kamila Moskowitzova, Borami Shin, David Blitzer, Caitlyn Rogers, Pedro J. del Nido, James D. McCully
Journal of Vascular Surgery2019
Objective: Acute limb ischemia (ALI), the most challenging form of ischemia-reperfusion injury (IRI) in skeletal muscle tissue, leads to decreased skeletal muscle viability and limb function. Mitochondrial injury has been shown to play a key role in skeletal muscle IRI. In previous studies, we have demonstrated that mitochondrial transplantation (MT) is an efficacious therapeutic strategy to replace or to augment mitochondria damaged by IRI, allowing enhanced muscle viability and function in cardiac tissue. In this study, we investigated the efficacy of MT in a murine ALI model. Methods: C57BL/6J mice (male, 10-12 weeks) were used in a model of ALI. Ischemia was induced by applying a tourniquet on the left hindlimb. After 2 hours of ischemia, the tourniquet was released, and reperfusion of the hindlimb was reestablished; either vehicle alone (n ¼ 15) or vehicle containing mitochondria (n ¼ 33) was injected directly into all the muscles of the hindlimb. Mitochondria were delivered at concentrations of 1 106 to 1 109 per gram wet weight to each muscle, and the animals were allowed to recover. Sham mice received no ischemia or injections but were anesthetized for 2 hours and allowed to recover. After 24 hours of recovery, limb function was assessed by DigiGait (Mouse Specifics Inc, Boston, Mass), and animals were euthanized; the gastrocnemius, soleus, and vastus medialis muscles were collected for analysis. Results: After 24 hours of hindlimb reperfusion, infarct size (percentage of total mass) and apoptosis were significantly decreased (P < .001, each) in the gastrocnemius, soleus, and vastus medialis muscles in MT mice compared with vehicle mice for all mitochondrial concentrations (1 106 to 1 109 per gram wet weight). DigiGait analysis at 24 hours of reperfusion showed that percentage shared stance time was significantly increased (P < .001) and stance factor was significantly decreased (P ¼ .001) in vehicle compared with MT and sham mice. No significant differences in percentage shared stance time (P ¼ .160) or stance factor (P ¼ .545) were observed between MT and sham mice. Conclusions: MT ameliorates skeletal muscle injury and enhances hindlimb function in the murine model of ALI. (J Vasc Surg 2019;-:1-13.) Clinical Relevance: Acute limb ischemia (ALI) is the most challenging form of ischemia-reperfusion injury (IRI), leading to loss of muscle viability and function. Mitochondria have been shown to play a key role in IRI. Previously, we have demonstrated that mitochondrial transplantation (MT) is an efficacious therapy to replace or to augment mitochondria damaged by IRI in cardiac tissue. In this study, we demonstrate that MT significantly decreases infarct size and apoptosis and significantly enhances hindlimb function in a murine model of ALI. MT provides a novel therapy for ALI, allowing preservation of muscle viability and muscle function.
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