ectopic catalase expression in mitochondria by adeno-associated virus enhances exercise performance in mice异位线粒体的过氧化氢酶表达腺相关病毒增强小鼠的运动性能.pdfVIP

Ectopic Catalase Expression in Mitochondria by Adeno- Associated Virus Enhances Exercise Performance in Mice 1 1 1 2 1 1 Dejia Li , Yi Lai , Yongping Yue , Peter S. Rabinovitch , Chady Hakim , Dongsheng Duan * 1 Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri, United States of America, 2 Department of Pathology, University of Washington, Seattle, Washington, United States of America Abstract Oxidative stress is thought to compromise muscle contractility. However, administration of generic antioxidants has failed to convincingly improve performance during exhaustive exercise. One possible explanation may relate to the inability of the supplemented antioxidants to effectively eliminate excessive free radicals at the site of generation. Here, we tested whether delivering catalase to the mitochondria, a site of free radical production in contracting muscle, could improve treadmill performance in C57Bl/6 mice. Recombinant adeno-associated virus serotype-9 (AV.RSV.MCAT) was generated to express a mitochondria-targeted catalase gene. AV.RSV.MCAT was delivered to newborn C57Bl/6 mouse circulation at the dose of 12 10 vector genome particles per mouse. Three months later, we observed a ,2 to 10-fold increase of catalase protein and activity in skeletal muscle and the heart. Subcellular fractionation western blot and double immunofluorescence staining confirmed ectopic catalase expression in the mitochondria. Compared with untreated control mice, absolute running distance and body weight normalized running distance were significantly improved in AV.RSV.MCAT infected mice during exhaustive treadmill running. Interestingly, ex vivo contractility of