Reactive oxygen species (ROS) are continuously produced by skeletal muscle from a number of mitochondrial and non-mitochondrial sources, with production being increased during contractile activity [
1]. Skeletal muscle fibers contain a well-developed endogenous antioxidant defence network consisting of the primary antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase, in addition to other antioxidant enzymes such as thioredoxins, glutaredoxins and peroxiredoxins, and nonenzymatic antioxidants, such as glutathione [
1]. Under most conditions, these cellular antioxidants work as a complex unit to regulate ROS, maintain oxidative balance and protect cells against oxidative damage. However, prolonged exposure to high levels of ROS can overwhelm the antioxidant defense system leading to oxidative damage of proteins, nucleic acids and lipids, resulting in cellular dysfunction, and has been associated with the pathogenesis of muscle related diseases such as type 2 diabetes, cachexia, and several dystrophies [
2,
3,
4,
5], as well as impaired exercise performance and recovery [
1,
6,
7]. For this reason, the use of oral antioxidant supplements to support the endogenous antioxidant defence system has received much attention as a potential strategy to limit oxidative stress and promote muscle health and performance [
1,
7,
8]. Somewhat paradoxically, ROS are increasingly being recognised as important signalling molecules that regulate skeletal muscle function and adaptation, and are required for optimal cell functioning [
9,
10,
11,
12]. As such, it is probably not surprising that supplementation with non-targeted antioxidants have had little impact on disease development and progression [
9,
13,
14,
15] and exercise performance [
16,
17] and in some instances have been reported to be deleterious [
18,
19,
20,
21]. This has driven the development of inhibitors [
4,
11,
22,
23] and cellular organelle-targeted antioxidants that are aimed at decreasing ROS levels from specific production sites in the cell.
It is clear that skeletal muscle produces ROS from numerous subcellular sites in a controlled and regulated manner in response to physiological stimuli, and may become unregulated under pathophysiological stimuli. The mitochondria have been cited as the major site of superoxide production in skeletal muscle, with approximately 0.15% of the oxygen consumed by the mitochondria undergoing one electron reduction to generate superoxide [
24]. A number of potential alternative sites of ROS production have been identified including nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanthine oxidases, and phospholipase A2 dependent processes. It is beyond the scope of this review to discuss the production of ROS from these non-mitochondrial sources, and readers are directed to the following comprehensive reviews [
1,
25]. The production of ROS from these non-mitochondrial sources appears to be linked to the signalling processes that modulate skeletal muscle adaptation, whereas excess mitochondrial ROS are more often associated with oxidative damage and disease states [
26,
27,
28]. There has been extensive research focusing on transgenic mice with targeted overexpression of the human catalase gene to mitochondria, which has highlighted the role of mitochondrial ROS production in numerous disease states [
29,
30,
31]. As a result, mitochondria-targeted antioxidants are increasingly being developed as a potential strategy to limit mitochondrial ROS production and oxidative damage, potentially without suppressing ROS that are important for signalling, and are becoming more widely available as an over the counter supplement. Compared with general antioxidants, mitochondria-targeted antioxidants are chemically modified to enable their transport across biological membranes where they accumulate several-hundred fold within the mitochondria and decrease ROS [
32]. The purpose of this review is to discuss the literature that relates to exogenous mitochondria-targeted products that primarily act as antioxidants, specifically, MitoQ (10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl) triphenylphosphonium mesylate), and SkQ1 (10-(6′-plastoquinonyl) decyltriphenylphosphonium), which are antioxidants that are targeted to the mitochondria, as well as the mitochondria locating peptides SS-31 (d-Arg-2′, 6′-dimethyltyrosine-Lys-Phe-NH
2) and XJB-5-131, and their effects on muscle function.