The production of ROS by skeletal muscle during exercise is associated with the onset of muscular fatigue and a reduction in athletic performance (12). Our study provides evidence to suggest that oral supplementation of the mitochondria-targeted antioxidant MitoQ can improve cycling time trial performance in middle-aged, recreationally trained male cyclists. The improvement in time trial performance observed in this study occurred along with an attenuation of exercise-induced increases in plasma F2-isoprostanes by MitoQ.
This is the first study to investigate the effect of MitoQ supplementation on cycling performance. Several studies have described improvements in cycling performance following supplementation with non-mitochondria-targeted coenzyme Q10 (28–31), which may improve performance by acting as an antioxidant within skeletal muscle mitochondria. However, accumulation of orally ingested coenzyme Q10 within mitochondria is limited by its poor bioavailability, which may explain why several others have failed to show improved performance following coenzyme Q10 supplementation (8, 32–35). Indeed, supplementation with coenzyme Q10 is often ineffective at increasing its concentration within skeletal muscle (36–38), and several studies have shown that coenzyme Q10 supplementation does not affect exercise-induced increases in systemic markers of oxidative stress (28, 39, 40). MitoQ has been shown accumulate in skeletal muscle following oral administration in mice (41). However, studies investigating the accumulation of MitoQ within skeletal muscle following oral supplementation in humans are needed.
The smallest worthwhile enhancement for cyclists competing in road time-trials has been reported to be 0.6% (42). Therefore, the 1.3% improvement in time trial performance observed following MitoQ supplementation in this study indicates a meaningful performance improvement. However, there was significant interindividual variability in the response to MitoQ, meaning we saw a small effect of MitoQ on time trial performance (d = 0.2). Individual redox status seems to be an important determinant of the efficacy of antioxidant supplementation to improve performance (43). We observed large interindividual variability in resting F2-isoprostanes and the redox response to exercise. However, there was no correlation between resting F2-isoprostanes or exercise-induced changes in F2-isoprostanes and change in time to complete the time trial following MitoQ supplementation compared to placebo. It should be noted that this study was not statistically powered for this outcome measure and it is important to investigate this further given that the ergogenic effects of vitamin C and N-acetylcysteine may be limited to individuals in which a specific deficiency is reversed (17). Whether the ergogenic effects of MitoQ are limited to individuals with low levels of endogenous ubiquinone poses an interesting avenue for further investigation.
In contrast to our finding that MitoQ supplementation improves cycling performance, the mitochondria-targeted antioxidant SS-31 did not affect force production during fatiguing stimulation in isolated mouse skeletal muscle (44) or the rate of contractile force decline in intact single muscle fibres (45). Direct comparisons between SS-31 and MitoQ are difficult given that SS-31 binds to the mitochondrial lipid cardiolipin and protects against oxidative damage whereas MitoQ protects cell membranes by acting as a chain breaking antioxidant and recycling α-tocopherol (24, 46). However, the ergogenic effect of MitoQ may be related to the impact of MitoQ on peripheral tissues, which would not be observed in an in vitro model of muscle contraction. MitoQ has been shown to improve endothelial function in older individuals with endothelial dysfunction (47). Whether these effects translate to healthy, physically trained individuals during exercise has not been investigated. Alternatively, the effects of mitochondria-targeted antioxidant supplementation on performance may be dependent on the mode and intensity of muscular contraction. Exercise-induced ROS production by skeletal muscle is thought to increase in an intensity-dependent manner (48), which may explain why we saw an improvement in performance during high intensity exercise following MitoQ supplementation while the physiological response to cycling at 70% VO2peak was unchanged. On the other hand, the higher plasma lactate concentration coupled with improved time trial performance with MitoQ suggests that MitoQ may improve performance by allowing for increased use of anaerobic metabolism during high intensity exercise, or by improving tolerance to lower pH in skeletal muscle. Future studies should aim to clarify whether the positive effects of MitoQ on performance and markers of exercise-induced oxidative stress are limited to exercise at a high intensity.
A major finding of the current study is that MitoQ attenuated the increase in plasma F2-isoprostanes during the time trial, which may indicate a protective effect of MitoQ against exercise-induced lipid peroxidation within mitochondria. Mitochondrial lipids are essential for maintaining the integrity of mitochondrial membranes and proper function of mitochondria; however, they are prone to lipid peroxidation by free radicals (49). Therefore, by attenuating exercise-induced lipid peroxidation in mitochondria, MitoQ may preserve the structure and dynamics of mitochondrial membranes and the efficiency through which mitochondria can supply ATP for muscular contraction. However, plasma F2-isoprostanes are a systemic marker of lipid peroxidation, meaning the post-exercise increase in plasma F2-isoprostane levels may also be derived from non-mitochondrial sources. Similar to previous studies (50, 51), we saw no effect of MitoQ on pre-exercise markers of oxidative stress. However, given that the participants were healthy and exercise-trained, it seems likely that any changes in resting F2-isoprostanes would have been difficult to detect (52). It appears that MitoQ may be most effective in lowering oxidative stress in situations where mitochondria are under stress (53).
Our study has limitations that should be acknowledged. Participants were all recreationally trained men and caution should be taken when extrapolating these results to elite athletes and females. Furthermore, the inclusion of a performance test at the start of each supplementation phase would have enabled us to ensure that any lasting effects of MitoQ supplementation were not carried over. A 6-week washout period has been shown to reverse the effects of MitoQ supplementation on mitochondrial H2O2 levels (50). However, we cannot be sure that MitoQ supplementation did not result in adaptations that may have lasted beyond the washout period. Participants also supplemented for 28 days while maintaining their habitual training meaning we cannot determine whether the improved cycling performance reflects an ergogenic effect of MitoQ on exercise performance alone or an interaction between MitoQ and training.