Rebuttal from Stuart M. Phillips and Chris McGlory.

Abstract

In our opponents’ view (Reid et al. 2014), the exact answer to the question of what is the dominant mechanism remains unknown and, as they conclude, ‘…proteolysis is an essential component of disuse atrophy.’ Importantly, we agree with both points. However, our position remains that the answer as to which is the dominant mechanism cannot merely be obtained from static protein/gene measurements or from rodent knock out models. As we in our original manuscript, and others (Cunningham, 2002) have highlighted, there are marked interspecies differences between humans and rodents that we propose have a significant bearing on this debate. While important proof of concept mechanistic information can be derived from rodent models they are still methodologically flawed. For example, the continued use of ex vivo muscle preparation is inherently biased towards showing elevated rates of muscle protein breakdown (MPB) and proteolytic markers as the tissue is essentially dying (albeit slowly) during the experiment. Our opponents cite only a single human study that attempted to measure MPB to support their argument (Tesch et al. 2008), which relied on an indirect proteolytic marker, and which did not include concomitant assessments of muscle protein synthesis (MPS). Even in recent papers (Bodine & Baehr, 2014) where large volumes of data were reviewed, in very few cited studies were actual rates of protein synthesis and/or breakdown even reported; instead, the change in muscle mass was estimated, proteolytic ‘markers’ were measured and a ‘conclusion’ reached as to the mechanism. To clarify, we do not dismiss our opponents’ argument that at least in the early phase of muscle disuse (<10 days), increases in MPB contribute to the decline in skeletal muscle size (Wall et al. 2013). There is evidence (with indirect markers) for this assertion, even in humans (Tesch et al. 2008). Nonetheless, the decline in human muscle size with disuse is predominantly driven by a reduction in the rate of MPS, especially in response to contraction and nutrition. Our opponents’ use of a graphic word cloud to support their thesis, while intriguing, is not in our view evidence that they are correct. Instead, we view this graphic ‘evidence’ as a depiction of the number of animal- versus human-based researchers in this area. Since animal-based researchers have generated most of the data in this field, the use of a word cloud in this instance is simply a reflection of the conclusion of the majority of researchers, using the same model, in this field. Thus, the word cloud is analogous to someone shouting the loudest in an argument and believing that approach renders their argument correct.