Acta PhysiologicaVolume 208, Issue 1,
A role for reactive oxygen species in the regulation of skeletal muscle hypertrophy
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 con-
troversy 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 support-
ing 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 follow-
ing a period of muscle overload, for example, follow-
ing 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 antioxi-
dant vitamin C, attenuated skeletal muscle hypertro-
phy 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) demon-
strate that the highly reactive oxidant, peroxynitrite,
which is formed by superoxide with nitric oxide, regu-
lates 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 follow-
ing overload, although not to the same extent as the
vitamin C-treated animals. This is likely a compensa-
tory increase in antioxidant defences within skeletal
muscle of the placebo group in response to the oxida-
tive 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). There-
fore, the increased skeletal muscle vitamin C levels in
the placebo group highlight, as the authors point out, a
limitation with the roden t 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 supplemen-
tation 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 supplemen-
tation 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
//onlinelibrary.wiley.com/doi/10.1113/expphysiol.2009.050526/fullReactive oxygen species and skeletal muscle adaptation to exercise
Physical exercise promotes signalling responses in skeletal muscle leading to alterations in protein synthesis and muscle phenotype. For example, as few as five consecutive days of endurance exercise (i.e. 60 min day−1 at 60% of maximal oxygen uptake) promotes an increase in both mitochondrial enzymes and antioxidants in the active skeletal muscles (Vincent et al. 2000). The fact that ROS are generated in contracting muscles and many signalling pathways are redox sensitive has raised the question of whether contraction-induced ROS production plays an essential role in skeletal muscle adaptation to aerobic exercise training. The short answer to this question is yes, and evidence to support this position follows.
Davies and colleagues provided the first suggestion that ROS production is a stimulus for skeletal muscle adaptation to exercise training (Davies et al. 1982). Since this initial proposal, many studies have supported this concept. For example, abundant in vitro studies have demonstrated that exposure of cultured myotubes to oxidants (e.g. hydrogen peroxide) promotes the expression of numerous genes (Li et al. 2003; McArdle et al. 2004; Hansen et al. 2007; Irrcher et al. 2009; McClung et al. 2009). Specifically, hydrogen peroxide exposure has been shown to augment the expression of key antioxidant enzymes in myotubes (Franco et al. 1999). Moreover, a recent study reveals that exposure of myotubes to exogenous hydrogen peroxide increases peroxisome proliferator-activated receptor-γ coactivator-1 protein-α (PGC-1α) promoter activity and mRNA expression (Irrcher et al. 2009). Importantly, both effects were blocked when the antioxidant N-acetylcysteine was added to the culture medium. It has also been reported that ROS production is a requirement for contraction-induced gene expression of PGC-1α in primary rat muscle cells (Silveira et al. 2006). Collectively, these in vitro experiments demonstrate that ROS are capable of altering gene expression in cultured muscle cells.
Similar to the aforementioned cell culture studies, numerous reports support the concept that exercise-induced ROS production alters muscle gene expression and contributes to exercise-induced adaptations of skeletal muscle in vivo. A common approach in many of these studies is to abolish the signalling effects of exercise-induced ROS production in skeletal muscle by treating animals or humans with antioxidants. For example, two independent reports have demonstrated that exercise-induced expression of heat shock protein 72 in rat skeletal and cardiac muscle is suppressed by antioxidant supplementation (Hamilton et al. 2003; Jackson et al. 2004). Also, two independent studies have recently concluded that antioxidant supplementation can retard important training adaptations in human skeletal muscle (Gomez-Cabrera et al. 2008; Ristow et al. 2009). Specifically, Gomez-Cabrera et al. (2008) reported that oral administration of vitamin C in humans prevented exercise-induced expression of PGC-1α and mitochondrial biogenesis in skeletal muscle. Furthermore, vitamin C treatment also prevented exercise-induced expression of several antioxidant enzymes in muscle (Gomez-Cabrera et al. 2008). Similar results in humans have been reported by Ristow et al. (2009). Together, these findings support the conclusion that ROS production plays an essential role in exercise-induced skeletal muscle adaptation.
Maybe its time to shelf NAC..