Human skeletal muscle wasting in hypoxia: a matter of hypoxic dose?

TO THE EDITOR: The authors of the Viewpoint (2) propose that a cut-off point for initiation of hypoxia-induced muscle wasting is ~5,000 km·h. Although they employ a valuable new metric, incorporating elevation and total exposure time, we previously suggested that it might be better to quantify the hypoxic stimuli by using “saturation hours” (4). This is particularly important given that both (de)saturation and oxidative/nitrosative stress responses to hypoxia are highly variable between individuals and also differ between the types of hypoxia (i.e., hypobaric vs. normobaric) (3). It is well established that the level of desaturation importantly modulates oxidative stress and, moreover, that augmented oxidative stress levels significantly contribute to disuse muscle atrophy by increasing protein oxidation and accelerating muscle protein breakdown (5). In addition, reactive oxygen species were shown to stabilize HIF-1 , independently of hypoxic stimulus, which likely plays a role in downregulation of muscle mass, as outlined in the Viewpoint (2). The close relationship between oxidative/nitrosative stress and muscle atrophy observed in cachexia and sarcopenia patients (1) lends further support to this notion. The individual variability in responses to hypoxia must therefore be taken into account to enhance our understanding of the mechanism underlying hypoxia-related muscle wasting. To conclude, it seems unlikely that a critical hypoxic threshold for muscle wasting could be defined solely on the “external” hypoxic dose, without accounting for the between-individual variability in desaturation (i.e., hypoxic stimuli) and/or oxidative/nitrosative stress responses.