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

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.

Two simple, direct, published, and undisputed observations document the first point. They are that, when the inspired O₂ fraction () is acutely altered (in random order within a single day):

1. is higher in hyperoxia and lower in hypoxia, compared to room air (Welch, 1982, 1987; Knight et al. 1993).

2. Muscle venous blood still contains significant amounts of O₂ at , in hypoxia, normoxia and hyperoxia (Roca et al. 1989; Knight et al. 1993).

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 & Thews, 1990), frozen myoglobin spectroscopy (Gayeski & Honig, 1988) and magnetic resonance spectroscopy (Richardson et al. 1995).

Scientific progress calls for not only supporting one’s views with data, but also reconciling them with other views. The major difference with others’ opinions is in understanding the role of cardiac output in limiting . That cardiac output contributes to limitation is not in dispute. Pericardiectomy in dogs increases maximal cardiac output and (Stray-Gundersen et al. 1986). The Saltin group, comparing two-legged and one-legged cycling (Rowell et al. 1986), showed that specific is higher in one-legged than two-legged cycling, associated with higher specific muscle blood flow. Additionally, Powers et al. (1989) showed that pulmonary gas exchange inefficiency affected ; 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.

The simplest way to understand how the O₂ transport system works, with every step contributing to limiting , is graphically, using a diagram relating to muscle venous on the basis of the two main transport equations involved. One underlies the previously mentioned Fick principle (O₂ uptake = blood flow × arteriovenous [O₂] difference), i.e.

1

And the second is the equation underlying the Fick law of diffusion:

2

is muscle O₂ diffusional conduc-tance, is mean microvascular within muscle, and is mitochondrial , which appears to be so low compared to (Richardson et al. 1995) that it can here be neglected. Because and muscle venous rise and fall in proportion to one another (Roca et al. 1989), we can replace by , the venous , times a constant, say, k. With these approximations, eqn 2 may be re-written:

3

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 .

Figure 1.

Determinants of

Plot of O₂ consumption () against muscle venous showing the two conservation of mass equations describing convective flow of O₂ into the muscle microcirculation (Fick principle), and subsequent diffusive flow of O₂ from the microcirculation to the mitochondria (Fick law of diffusion). Conservation of mass occurs only at their point of intersection, indicating the value of when the independent variables , and are those at (modified from Wagner, 1996).

Call for comments

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.

Biography

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 ismuscle capillary growth regulation usingmolecular 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 skeletalmuscle structure and function.

Additional information

Competing interests

The author has no conflicts of interest associated with this manuscript.

Funding

Funding was provided by NIH HL091830.