CrossTalk proposal: Diffusion limitation of O2 from microvessels into muscle does contribute to the limitation of Vo2max

At maximal oxygen uptake () we know that (1) muscle O2 extraction is not 100%, yet (2) hyperoxia increases . The reason for (1) is diffusion limitation of O2 from the muscle microvessels to the mitochondria. This does not exclude ‘central’ factors from also affecting , as will be explained. This shows unequivocally that the muscles are capable of using more O2 in normoxia (or hypoxia) than they can extract, proving the existence of an extraction limit, contributing to limitation. The extraction limit could result from any of three possibilities: (a) shunting of arterial blood around exercising muscle; (b) heterogeneity in the distribution of blood flow with respect to metabolic demand; (c) diffusion limitation of O2 transport from microvessels to mitochondria. While there may be minor contributions from the first two, diffusion limitation appears to be the major basis of limited extraction. The most compelling evidence comes from studies of isolated in situ, canine gastrocnemius muscle in which maximal contractions (and ) were produced by nerve stimulation, holding O2 delivery into the muscle constant while one factor was varied – haemoglobin O2 affinity defined by (P50) (Hogan et al. 1991; Richardson et al. 1998). Arterial O2 and blood flow were kept constant (animals breathed 100% O2; muscle blood flow was pump-controlled). Hogan's study reduced P50 (to impair diffusive extraction by reducing microvascular ); Richardson's study increased P50 (to enhance diffusive extraction by increasing microvascular ). Importantly, neither shunting nor heterogeneity would alter extraction at constant O2 delivery and blood flow, as only P50 is varied. As predicted, increased as P50 was raised, and fell when P50 was reduced. Moreover, the amount by which changed was predicted by the laws of diffusion from the concomitant changes in mean microvascular : was proportional to mean microvascular , a finding also noted in humans (Roca et al. 1989; Knight et al. 1993). Additional evidence for diffusion limitation of O2 between muscle microvessels and mitochondria comes from com-putational modelling (Groebe severe anaemia is also well known to reduce exercise capacity. That is exactly what would be expected of an in-series O2 transport system – every step must play a role in affecting overall outcome (). Pro-cardiac-output-is-the-limiting-factor-advocates (PCOITLFA) cite the Fick principle (O2 uptake = blood flow × arteriovenous O2 difference) applied to elite athletes versus the rest of us. The main, undisputed, difference is in cardiac output (blood flow) and not in arteriovenous O2 difference. Ergo, the PCOITLFA conclude that cardiac output, not extraction, explains the differences in . What the PCOITLFA forget is that if all else were similar between us, the elite athlete's higher cardiac output would shorten red cell transit time for O2 unloading in the muscle microvessels. This would offset much of the benefit of higher blood flow by reducing diffusive O2 unloading (Wagner, 1996). However, despite higher blood flow, athletes are able to extract higher amounts of O2: femoral venous is usually lower than in the rest of us. This means that the athlete's diffusive conductance supporting O2 movement from microvessels to mitochondria is greater than in the rest of us, allowing the maintenance of a large arteriovenous O2 difference in the face of higher blood flow. But even so, elite athletes increase with added O2, which takes us back to the initial arguments of this article. Equations 1 and 3 embody the same undisputed law: conservation of O2 mass during its transport. As a consequence they apply simultaneously: at their solution, both and must be the same in the two equations. Because they both relate to muscle venous O2 levels, they can be plotted on one diagram with on the ordinate and on the abscissa (Fig. 1, modified from Wagner, 1996). Their intersection point is the only point where conservation of mass exists – the same at the same – indicating the value of for the given values of , and . Change any one of these three, and the lines will shift, yielding a different intersection point (i.e. different ). Since represents cardiac function, represents pulmonary gas exchange and blood Hb, and represents muscle O2 diffusional properties, it is evident that all steps of the O2 pathway significantly impact . That is how an in-series system must work, and why muscle O2 diffusion limitation does contribute to limitation of . 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. Peter Wagner is Distinguished Professor of Medicine and Bioengineering at the University of California, San Diego. His research addresses the theoretical and experimental basis of oxygen transport and its limitations in the lungs and skeletal muscles in health and disease. A particular focus is muscle capillary growth regulation using molecular biological approaches in integrated systems: the role of O2, microvascular haemodynamics, physical factors, nitric oxide and inflammatory mediators in transcriptional regulation of angiogenic growth factors. Of particular interest is the role of VEGF in both pulmonary and skeletal muscle structure and function. 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.