Mitochondria-Targeted Antioxidants and Skeletal Muscle Function

Abstract

One of the main sources of reactive oxygen species (ROS) in skeletal muscle is the mitochondria. Prolonged or very high ROS exposure causes oxidative damage, which can be deleterious to muscle function, and as such, there is growing interest in targeting antioxidants to the mitochondria in an effort to prevent or treat muscle dysfunction and damage associated with disease and injury. Paradoxically, however, ROS also act as important signalling molecules in controlling cellular homeostasis, and therefore caution must be taken when supplementing with antioxidants. It is possible that mitochondria-targeted antioxidants may limit oxidative stress without suppressing ROS from non-mitochondrial sources that might be important for cell signalling. Therefore, in this review, we summarise literature relating to the effect of mitochondria-targeted antioxidants on skeletal muscle function. Overall, mitochondria-targeted antioxidants appear to exert beneficial effects on mitochondrial capacity and function, insulin sensitivity and age-related declines in muscle function. However, it seems that this is dependent on the type of mitochondrial-trageted antioxidant employed, and its specific mechanism of action, rather than simply targeting to the mitochondria.

Keywords: antioxidant; mitochondria; oxidative stress; reactive oxygen species; skeletal muscle.

Figure 1

Accumulation and antioxidant mechanism of 10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl) triphenylphosphonium mesylate (MitoQ) (A) and 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SkQ1) (B). Driven by the plasma membrane potential (Δψ_p), MitoQ and SkQ1 pass through the plasma membrane and accumulate 5-10 fold within the cytosol. MitoQ and SkQ1 then accumulate several-hundredfold within the mitochondria driven by the mitochondrial membrane potential (Δψ_m).Within the mitochondria, MitoQ is reduced to ubiquinol and SkQ1 is reduced to SkQH₂ by the respiratory chain. In acting as an antioxidant, ubiquinol is oxidised to ubiquinone and SkQH₂ is oxidised to SkQ1, both of which are rereduced by the respiratory chain. MitoQ is effective at preventing lipid peroxidation. SkQ1 is effective at preventing peroxidation of cardiolipin and inhibits the production of superoxide. (adapted from Murphy and Smith, 2007 [39]).

Figure 2

Accumulation and antioxidant mechanism of Szeto-Schiller-31 (SS-31) (A) and XJB-5-131 (B). SS-31 accumulates several-thousand fold within the mitochondria where it binds to cardiolipin. In acting as an antioxidant, it is likely that SS-31 prevents peroxidation of cardiolipin and decreases mitochondrial ROS production. XJB-5-131 accumulates within the mitochondria independent of the membrane potential, where it acts as an antioxidant by scavenging mitochondrial ROS.

Figure 3

The effect of mitochondria-targeted antioxidants on parameters of skeletal muscle function. The mitochondria-targeted antioxidants MitoQ and SkQ1, and the mitochondria-locating peptides SS-31 and XJB-5-131 accumulate within the inner membrane of the mitochondrion, where they decrease ROS. Mitochondria-targeted antioxidants have a beneficial effect on insulin sensitivity and age-related declines in muscle function (indicated by green squares). However, their effects on mitochondrial biogenesis and function and skeletal muscle contractile function are still unclear (indicated by white squares).