Muscle mitochondrial capacity exceeds maximal oxygen delivery in humans Robert Boushel a,c, ⁎, Erich Gnaiger b , Jose A.L. Calbet a , Jose Gonzalez-Alonso a , Cynthia Wright-Paradis a , Hans Sondergaard a , Ignacio Ara a , Jørn W. Helge a,c , Bengt Saltin a a The Copenhagen Muscle Research Centre, Copenhagen, Denmark b Department of Transplant Surgery, Medical University of Innsbruck, Austria c Centre for healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Denmark abstract article info Article history: Received 2 March 2010 Received in revised form 4 November 2010 Accepted 3 December 2010 Available online 13 December 2010 Keywords: Mitochondria Oxygen uptake Exercise Oxygen delivery Humans Across a wide range of species and body mass a close matching exists between maximal conductive oxygen delivery and mitochondrial respiratory rate. In this study we investigated in humans how closely in-vivo maximal oxygen consumption (VO 2 max) is matched to state 3 muscle mitochondrial respiration. High resolution respirometry was used to quantify mitochondrial respiration from the biopsies of arm and leg muscles while in-vivo arm and leg VO 2 were determined by the Fick method during leg cycling and arm cranking. We hypothesized that muscle mitochondrial respiratory rate exceeds that of systemic oxygen delivery. The state 3 mitochondrial respiration of the deltoid muscle (4.3 ± 0.4 mmol o 2 kg -1 min -1 ) was similar to the in-vivo VO 2 during maximal arm cranking (4.7 ± 0.5 mmol O 2 kg -1 min -1 ) with 6 kg muscle. In contrast, the mitochondrial state 3 of the quadriceps was 6.9 ± 0.5 mmol O 2 kg -1 min -1 , exceeding the in- vivo leg VO 2 max (5.0 ± 0.2 mmol O 2 kg -1 min -1 ) during leg cycling with 20 kg muscle (P b 0.05). Thus, when half or more of the body muscle mass is engaged during exercise, muscle mitochondrial respiratory capacity surpasses in-vivo VO 2 max. The findings reveal an excess capacity of muscle mitochondrial respiratory rate over O 2 delivery by the circulation in the cascade defining maximal oxidative rate in humans. © 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved. 1. Introduction In humans, the rest to work transition during dynamic exercise results in increases of oxygen (O 2 ) consumption of up to 10–20 fold at peak work capacity (Hermansen and Saltin, 1969; Mitchell et al., 1958). The extent to which maximal oxygen consumption (VO 2 max) reflects that all components of the oxygen cascade from the systemic circulation to the mitochondria have equal capacities is debated. Taylor and Weibel (1981) advanced the concept of symmorphosis, postulating that all major physiological components of the O 2 cascade determining an organism's maximal VO 2 are proportionately designed. This concept is supported by the study of allometric and adaptive variation across a wide range of species where VO 2 max per body weight scales with invariant ratios of mitochondria, capillaries, heart volume and lung diffusion capacities per ml O 2 consumed in the organism. In species ranging from 20 g to 500 kg of body mass, mitochondrial volume in skeletal muscle varies very closely (r 2 =0.97) with VO 2 max, and the organism consumes ~4–5 ml O 2 ml -1 mitochondrial volume (Hoppeler and Weibel, 1998; Schwerzmann et al., 1989). The modelled values are based on the whole organism mass, estimates of volume density of muscle mitochondria determined by microscopy, and polarographic measures of muscle mitochondrial respiration (Schwerzmann et al., 1989). Across species, the mitochondrial volume is consistently ~0.58% of the body mass (Hoppeler and Weibel, 1998). These comparative data suggest that the mitochondrial volume is a major determinant of VO 2 max in the organism. However, bipeds (humans) may be an exception, having an apparent excess mitochondrial volume to VO 2 max relationship and a low heart volume to body mass ratio (10 ml kg -1 body mass) compared to quadripeds ranging from mice to cows with high-to-low aerobic power (Gunn, 1989; Keul et al., 1982; Prothero, 1979). In humans, the heart mass as a function of the body mass is 0.33% whereas it is 0.6% in the cow and camel, 1.04% in the thoroughbred horse and 1.5% in the greyhound (Gunn, 1989). The morphometric pattern of the low heart size in humans likely resulted from evolutionary adaptations to the upright posture whereby central cardiovascular structures and the capacity for O 2 delivery only partly meet muscle oxidative capacity compared to the highly aerobic species such as the pronghorn antelope (Lindstedt et al., 1991). The recent work on mitochondrial respiratory capacity in human skeletal muscle employing both isolated mitochondria and permeabilized fiber models indicate that the mitochondrial O 2 flux capacity may be ~ 1.6-fold higher than the previous estimates when the substrate supply to mitochondria is optimized (Boushel et al., 2007; Rasmussen et al., 2001). When evaluated at kinetic oxygen saturation, excess capacity of mitochondria may conform to optimum design in the oxygen consumption cascade in Mitochondrion 11 (2011) 303–307 ⁎ Corresponding author. Department of Biomedical Sciences, Division of Systems Biology, Panum Institute 12.4.40, University of Copenhagen, Begdamsvej 3 DK 2200 Copenhagen N, Denmark. Tel.: +45 28 75 7430; fax: +45 35 32 7420. E-mail address: boushel@sund.ku.dk (R. Boushel). 1567-7249/$ – see front matter © 2010 Elsevier B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/j.mito.2010.12.006 Contents lists available at ScienceDirect Mitochondrion journal homepage: www.elsevier.com/locate/mito