A role for reactive oxygen species in the regulation of skeletal muscle hypertrophy

Abstract

It is clear that at pathologically high chronic levels, reactive oxygen species (ROS) are cytotoxic. However, it is also now clear that during contraction ROS are produced at low (physiological) levels and play an important role in cell signalling in normal healthy skeletal muscle (reviewed in Powers & Jackson 2008). To date, much of the work regarding skeletal muscle ROS produced during contraction has focussed on endurance exercise. This has led to considerable controversy in the literature regarding the potential for antioxidant supplements to prevent skeletal muscle adaptations to endurance training, such as increased mitochondrial biogenesis, with some studies supporting such a role (Gomez-Cabrera et al. 2008, Ristow et al. 2009), whilst others do not (Yfanti et al. 2010, Higashida et al. 2011, Strobel et al. 2011). Hypertrophy is a skeletal muscle adaptation following a period of muscle overload, for example, following resistance exercise training. Makanae et al. (2013) now suggest a role for ROS as a regulator of skeletal muscle hypertrophy following muscle overload. The authors used the well-established rodent model of mechanically overloading the plantaris by surgically removing the synergistic gastrocnemius and soleus muscles of the hindlimb. As expected, two weeks following surgery, there was a significant increase in skeletal muscle hypertrophy. Makanae et al. (2013) also found that a high daily oral dose of the antioxidant vitamin C, attenuated skeletal muscle hypertrophy and oxidative stress, as measured by the ratio of oxidized to total glutathione. The findings of Makanae et al. are topical, because other very recent findings (Ito et al. 2013) demonstrate that the highly reactive oxidant, peroxynitrite, which is formed by superoxide with nitric oxide, regulates skeletal muscle hypertrophy induced by overload. Another interesting finding by Makanae et al. (2013) was that endogenous levels of skeletal muscle vitamin C were increased in the placebo group following overload, although not to the same extent as the vitamin C-treated animals. This is likely a compensatory increase in antioxidant defences within skeletal muscle of the placebo group in response to the oxidative stress. Indeed, levels of glutathione, one of the major nonenzymatic antioxidants in skeletal muscle (Powers & Jackson 2008), also significantly increased in response to overload (Makanae et al. 2013). Therefore, the increased skeletal muscle vitamin C levels in the placebo group highlight, as the authors point out, a limitation with the rodent model, because unlike humans, rats are able to synthesize their own vitamin C. Thus, the upregulation of skeletal muscle vitamin C levels in the placebo-treated group following surgery could also potentially explain why exogenous treatment of vitamin C only mildly attenuated the skeletal muscle hypertrophy. As mentioned earlier, considerable controversy exists as to whether high dose antioxidant supplementation prevents skeletal muscle adaptations following endurance training. However, the few human studies to investigate resistance training with antioxidants have shown no effect of vitamin C and E supplementation on skeletal muscle adaptations (Bobeuf et al. 2011, Theodorou et al. 2011), although this is not sufficient evidence in itself to exclude a role for ROS in the regulation of human skeletal muscle hypertrophy. Furthermore, these rodent studies (Ito et al. 2013, Makanae et al. 2013) are still quite relevant to humans, since understanding the molecular pathways that regulate muscle mass may provide important therapeutic targets for people with muscle wasting conditions. None to declare.