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 10(12) vector genome particles per mouse. Three months later, we observed a approximately 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 the extensor digitorum longus muscle was not altered. Taken together, we have demonstrated that forced
catalase expression in the mitochondria enhances exercise performance. Our result provides a framework for further elucidating the underlying mechanism. It also raises the hope of applying similar strategies to remove excessive, pathogenic
free radicals in certain muscle diseases (such as
Duchenne muscular dystrophy) and ameliorate muscle disease.