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J Physiol (2003), 551.2, p. 397
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2003.044412
Email: paul.greenhaff{at}nottingham.ac.uk
At the start of the 1980s, whilst I was still an undergraduate student, much scientific debate centred on the pattern, magnitude and time course of changes in muscle energy metabolism, blood flow and oxygen utilisation during short-lasting exercise in humans. These questions had been hotly debated for several decades. Firstly, because they were, and still are, central to our understanding of the integration of skeletal muscle energy metabolism at the onset of contraction. Secondly, because it was important for the elucidation of mechanisms responsible for fatigue development during contraction in humans. Milestones in this debate were reached with the publication of two classic papers in The Journal of Physiology in 1983 and 1985. The first, written by Eric Hultman and Hans Sjöholm, addressed the pattern of change in the skeletal muscle energy metabolism and tension development during the first minute of intense contraction (Hultman & Sjöholm, 1983; available online with this issue of The Journal of Physiology). The second, produced by Per Andersen and Bengt Saltin, addressed the changes in muscle blood flow and oxygen utilisation during exercise of different intensities (Andersen & Saltin, 1985; available online with this issue of The Journal of Physiology). Collectively, these papers documented significant technological advances and contributed enormously to our scientific understanding in the area, which, as might be expected, set the scene for a whole series of further important publications. It should also not go without comment that both papers originated from Scandinavia, a constant presence in the field of human metabolism and physiology.
If we return to the early 1980s, it was known that there were significant contributions from glycolysis and phosphocreatine (PCr) to ATP production at the onset of exercise, which increased with increasing contraction intensities (Hultman et al. 1967; Dawson et al. 1978). Nevertheless, the temporal changes in these energy delivery pathways at the onset of exercise were unknown. This did not, however, hinder the widespread acceptance that ATP production from glycolytic flux was not initiated until muscle PCr stores had been degraded. Furthermore, little was known about the relationship between ATP production rates from PCr and glycolysis and the loss of tension in human skeletal muscle during intense contraction. The paper of Hultman & Sjöholm addressed all these points in a systematic manner. To do this, the authors amalgamated the muscle electrical stimulation and functional measurement techniques developed for use in humans by Richard Edwards and colleagues (1977) with rapid and multiple muscle biopsy sampling during contraction. This approach provided the authors with the opportunity to achieve any predetermined degree of muscle activation and isometric tension development, whilst, at the same time, being able to biopsy the muscle frequently and in situ during contraction. This offered a significant advance because, as you are probably aware, it is not possible to maintain a voluntary contraction during the muscle biopsy procedure. The authors determined muscle isometric tension development in the knee extensors during 50 s of intense tetanic contraction during which time they obtained seven muscle biopsy samples. The major findings from this work were that the authors showed, for the first time in human skeletal muscle, very high rates of ATP production from PCr degradation and glycolysis, and that the rate of ATP turnover declined at approximately the same rate as the decline in muscle tension development. This led to the notion that fatigue during very intense exercise in humans may occur when the rate of ATP delivery cannot match the ATP demand of contraction, which has been the subject of many publications over the past 25 years. Finally, the authors were able to unequivocally demonstrate that glycolysis was initiated very early in contraction and long before PCr depletion, thereby putting an end to the dogma that PCr depletion initiates glycolysis.
The study of Hultman & Sjöholm required that limb blood flow was occluded prior to and during contraction, using a torniquet placed around the upper thigh, thereby achieving a closed muscle compartment and enabling muscle ATP production rates during contraction to be accurately calculated from muscle metabolite changes. It is clear therefore that the time course and magnitude of change in muscle blood flow during exercise in humans was not, and could not, be addressed. These questions, and others, were addressed in the landmark paper of Andersen & Saltin who, in their own words, 'defined the relationship between blood flow and oxygen uptake of one muscle group in man at various work intensities'. Progress in the area prior to the publication of the work of Andersen & Saltin had been hampered by limitations in the methodologies used to accurately estimate the mass of muscle recruited during contraction and to determine muscle blood flow during exercise in humans. One particularly appealing aspect of the work therefore is the comprehensive and elegant manner by which the authors addressed and overcame these limitations. Firstly, the authors developed a single leg exercise model that recruited only the quadriceps muscle group during exercise, which, due to its relatively small mass, also meant that blood flow would not be limited by central circulation during exercise, or by the dimensions of the feeding artery (Andersen et al. 1985). Secondly, the authors developed the constant infusion thermodilution technique, using an approach developed in the 1960s (Pavek et al. 1964), to determine blood flow changes in the exercising quadriceps muscle group. This involved a constant flow of cold saline (near to zero degrees centigrade) being introduced into the femoral vein, and blood flow being calculated from changes in the temperature of femoral blood during infusion. Because blood flow below the knee was occluded during the flow measurements, and because only the quadriceps muscle group was active, the combined power of these two approaches meant that the blood flow measurements made primarily reflected perfusion of the quadriceps muscle group. Using this elegant approach, along with arterial-venous difference measurements of muscle oxygen consumption and lactate release, the authors were able to show for the first time that muscle blood flow increases linearly with increased exercise workloads up to an extremely high maximal flow rate of about 2.5 l kg-1 min-1. The authors were also able to show that blood flow in general changes in parallel with the oxygen demand of contraction. Perhaps most importantly however, the authors clearly showed that oxygen delivery to contracting muscle is not limited by blood flow, at least under these experimental conditions, and that there can be considerable muscle lactate efflux in the presence of plentiful oxygen delivery. This work had a profound effect in changing the widely held belief that blood flow limits muscle oxygen delivery during exercise in humans, and thereby modulates muscle metabolism and, subsequently, fatigue development.
It is unquestionable that the papers of Hultman & Sjöholm and Andersen & Saltin acted as catalysts for a large body of subsequent work, and both papers are still widely cited today (indeed, the latter paper is currently the 7th most-cited paper published in The Journal of Physiology). It is also stimulating for younger workers in the field that the senior authors of these papers are still working with the same enthusiasm and commitment they showed 20 years ago! What value might these papers have for future research? Well, it is now obvious to many that the integrated approach to research that both papers gratifyingly demonstrate, if combined with relevant molecular-based approaches, holds the key to explaining how changes at a molecular level can modulate physiological function in humans.
Andersen P, Adams RP, Sjogaard G, Thorboe A & Saltin B (1985). J Appl Physiol 59, 1647-1653. [Abstract]
Andersen P & Saltin B (1985). J Physiol 366, 233-249. [Abstract]
Dawson MJ, Gadian DG & Wilkie DR (1978). Nature 274, 861-865. [Medline]
Edwards RHT, Young A, Hosking GP & Jones DA (1977). Clin Sci Mol Med 52, 283-290. [Medline]
Hultman E, Bergstrom J & Anderson MN (1967). Scand J Clin Lab Invest 19, 56-66. [Medline]
Hultman E & Sjoholm H (1983). J Physiol 345, 525-532. [Abstract]
Pavek K, Boska E & Selecky (1964). Circulation Res XV, 211-218.
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