Reply from Tyler Barker and Maret G. Traber


We thank the authors for their interest and Letter to the Editor regarding our recent Journal Club article (Barker & Traber, 2007).

The authors of the letter emphasize the wealth of information concerning the dynamic measures of protein turnover in human muscle during immobilization that lead to disuse atrophy, a point that is well taken and appreciated by us. We would also like to thank the authors for their succinct review identifying the significance of muscle protein synthesis on muscle mass in humans. While it is well known that muscle mass is governed by the balance between protein synthesis and degradation, it would be of great importance to identify the initiating event(s) or factor(s) that alter this balance and cause atrophy following limb disuse in humans. Furthermore, it is probably necessary to consider that there may be differences in responses from normal healthy individuals who have experienced a traumatic injury compared with those who have an illness, especially influenced by increased inflammation, when investigating the temporal regulation of the dynamics that govern muscle mass.

We agree with the authors' comment that there is very little direct support in humans regarding the influence of oxidative stress on muscle disuse atrophy. The intent of our conclusion was to stimulate the application of acquired scientific knowledge in experimental animals to humans for appropriate study design and hypothesis testing. Whether there is a local increase in oxidative stress prior to or during limb disuse atrophy in humans is unknown, and is the subject of our current research protocols.

Due to space limitations, we cited only one paper describing vitamin E amelioration of hindlimb suspension-induced muscle atrophy in rats (Servais et al. 2007). However, other papers have demonstrated the potential influence of vitamin E supplementation on the amelioration of atrophy following muscle disuse (Appell et al. 1997; Kondo et al. 1992b); in contrast, other experimenters have not found any vitamin E benefit on muscle mass (Koesterer et al. 2002). In addition, several excellent reviews have identified an association between oxidative stress and muscle atrophy (Powers et al. 2005, 2007; Reid et al. 2005). What made the findings by Servais et al. (2007) intriguing to us, was that vitamin E supplementation concurrently reduced muscle atrophy and various proteolytic pathways during limb disuse in rats. Furthermore, a variety of antioxidant supplements and/or experimental treatment methods that reduce oxidative stress in diverse animal models demonstrate that when the increase in oxidative stress is reduced during disuse (i.e. hindlimb suspension or mechanical ventilation) there is also a decrease in muscle atrophy (Kondo et al. 1992a; Ikemoto et al. 2002; Betters et al. 2004; Arbogast et al. 2006; McClung et al. 2007; Suzuki et al. 2007).

We agree that evidence demonstrating that oxidative stress is the initiating cause of muscle atrophy in humans would be very useful from both the clinical and ‘subclinical’ standpoint. However, as the authors point out, there is no evidence to date on human muscle disuse atrophy or whether there is an increase in oxidative stress, assessed either by increases in oxidative stress biomarkers or by changes in antioxidant concentrations in immobilized muscle. However, the increases in metallothionein and atrogin-1/MAFbx gene expression in humans (Urso et al. 2006, 2007) during disuse atrophy are provocative. The increase in metallothionein in both human (Urso et al. 2007, 2006) and animal (Kondo et al. 1992b) disuse studies suggests a common mechanism because metallothioneins are induced by oxidative stress and display antioxidant properties due in part to their ability to both scavenge reactive oxygen species and minimize the availability of pro-oxidant transition metals (Miles et al. 2000). The increase in atrogin-1/MAFbx during limb disuse in humans (Jones et al. 2004; Ogawa et al. 2006; Urso et al. 2006, 2007; Chen et al. 2007) further implicates oxidative stress because myotubes exposed to H2O2 have also been found to increase atrogin-1/MAFbx mRNA (Li et al. 2003). This finding is important because it identifies a discernable factor (i.e. oxidative stress) that may be initially responsible for the increase in a key enzyme in the ubiquitin proteasome pathway. This may probably occur through or in collaboration with the TNF-α/NF–κB pathway that is sensitive to reactive oxygen species (Li et al. 1998, 1999). Thus, a number of recent findings suggest that an imbalance in the responses to oxidative stress may be critical in the initiation of pathological responses to muscle immobilization.

The authors' letter regarding our recent Journal Club article (Barker & Traber, 2007) is appreciated not only for their scientific advice regarding the extrapolations from studies conducted in rodents and applied to humans, but also for their obvious expertise in muscle protein turnover. We believe that oxidative stress may be one of many causative links or ‘upstream driver’ in human muscle atrophy. But, this assertion remains an hypothesis to be tested.