Rebuttal from Peter D. Wagner.

Abstract

Lundby & Montero's claim that diffusion limitation does not affect (Lundby & Montero, 2015) is based essentially on two papers from the group where Lundby trained, papers they accept uncritically (Calbet et al. 2003, 2009), and the dismissal of two papers (Hogan et al. 1991; Richardson et al. 1998), which they assert are not to be believed because they contain false positive outcomes – a claim with which we disagree. They ignore Fig. 4F in Calbet et al. (2003) where, comparing normoxia (N) to chronic hypoxia (CH), leg is in fact directly proportional to mean leg capillary , precisely as predicted for diffusion limitation. Those same data show higher in normoxia than CH despite statistically identical arterial O2 concentrations (higher [Hb] in CH compensating for hypoxaemia), thereby dissociating O2 content from . Thus, this paper actually supports the importance of diffusion limitation. Lundby & Montero reasonably question metabolism/perfusion heterogeneity rather than diffusion limitation as constraining extraction, but recent work (Vogiatzis et al. 2015) shows minimal heterogeneity, which therefore is highly unlikely to be the explanation. The 2009 Calbet paper does not evaluate diffusion limitation, and accordingly cannot elucidate its role in limiting – absence of evidence is not evidence of absence. It does show higher [Hb] in CH restoring O2 delivery to normoxic values despite lower leg blood flow and arterial hypoxaemia. Piiper & Scheid (1981) showed how diffusive exchange depends on the compound ratio D/(β•) where D is diffusing capacity, β is the slope of the O2Hb dissociation curve and is blood flow. In CH, D probably increased because of higher [Hb], β also increased with [Hb], and was lower. Thus, it is entirely possible that D/(β•) increased, allowing extraction to increase to restore . What must be understood is that O2 transport, as an integrated system involving the lungs, heart, circulation and muscles, has to be analysed as a system: all components must be measured before any can be dismissed as unimportant. Assessing only selected steps sheds no light on those com-ponents not examined. There remains no argument about the importance of the lungs, heart and circulation in transporting O2 into the muscle vasculature, but the evidence is clear that the final transport step – diffusion of O2 from the vasculature to the mitochondria – is also an important contributor to limiting . Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘Last Word’. Please email your comment, including a title and a declaration of interest to jphysiol@physoc.org. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The author has no conflicts of interest associated with this manuscript. Funding was provided by NIH HL091830.