Accepted Article Received Date : 12-Jul-2016 Revised Date : 24-Oct-2016 Accepted Date : 28-Oct-2016 Article type : Review Article Biology of VO2max: looking under the physiology lamp Carsten Lundby1, David Montero2 & Michael Joyner3. 1 Zürich Center for Integrative Human Physiology, Institute of Physiology, University of Zürich, Switzerland; 2Department of Cardiology, University Hospital Zurich, Switzerland; and 3Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, USA Short title: Trainability of humans Correspondence: Prof. Carsten Lundby University of Zurich Institute of Physiology Winterthurerstrasse 190 CH-8057 Zurich Switzerland Tel: +41 44 635 50 52 Email: [email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/apha.12827 This article is protected by copyright. All rights reserved. Abstract Accepted Article In this review we argue that several key features of maximal oxygen uptake (VO2max) should underpin discussions about the biological and reductionist determinants of its inter-individual variability: 1) Training induced increases in VO2max are largely facilitated by expansion of red blood cell volume and an associated improvement in stroke volume, which also adapts independent of changes in red blood cell volume. These general concepts are also informed by cross sectional studies in athletes that have very high values for VO2max. Therefore, 2) variations in VO2max improvements with exercise training are also likely related to variations in these physiological determinants. 3) All previously untrained individuals will respond to endurance exercise training in terms of improvements in VO2max provided the stimulus exceeds a certain volume and/or intensity. Thus genetic analysis and/or reductionist studies performed to understand or predict such variations might focus specifically on DNA variants or other molecular phenomena of relevance to these physiological pathways. Key words: Exercise, genetics, mitochondria, non-responders, performance, red blood cell volume. Introduction: Physiology, Reductionism & Street Lamps Maximal oxygen uptake (VO2max) and its closely related clinical correlate cardiorespiratory fitness are key determinants of both elite performance in endurance sports and mortality in the general population (Pedersen and Saltin, 2015). In this review we argue the dominant and deterministic physiological pathways that account for a vast majority of inter-individual variability in VO2max are well known and center on total body hemoglobin content and peak cardiac stroke volume and as a result cardiac output. In this context, searches for reductionist explanations and more basic biological factors that might contribute to inter-individual variability in VO2max and its response to training should focus on these physiological pathways. We adapt the “street lamp parable” to highlight our position. In the street lamp parable an intoxicated individual is searching for a set of lost keys under the street lamp because that is where “the light is”. In most cases the street lamp parable is a cautionary tale about observational bias. By contrast, in the case of VO2max failure to focus where the physiological light has led to limited insight about any DNA variants and other molecular This article is protected by copyright. All rights reserved. mechanisms the might contribute to this critical physiological phenotype. Additionally, we hope to use this physiological “light” to discuss two types of studies that seek to understand Accepted Article the basic biology underpinning VO2max. One type is cross sectional studies including elite athletes who have decidedly extreme phenotypes due to whatever biological endowment they possess plus years of prolonged and intense training. The other type of study is the classic short term intervention in “average” citizens that seeks to understand the phenotypic changes associated with periods of exercise training lasting a few months. Red cell mass, total body hemoglobin, blood volume and stroke volume explain interindividual differences in VO2max Figure 1 illustrates the clear relationship between VO2max expressed in l.min-1 and cardiac output (l) and red blood cell mass (ml). Additionally acute interventional maneuvers that alter these variables also typically alter VO2max in a way (Calbet et al., 2006b) consistent with these cross sectional data. The key points of Figure 1, and we start our review with them, are that the physiological pathways that dominate the determinants of VO2max are well known and in a statistical context explain a very high fraction of the population variance. The clarity of these physiological relationships is in stark contrast to studies on larger cohorts of elite endurance athletes that show no clear genetic explanation for these findings (Rankinen et al., 2016). By contrast Finnish cross country skier Eero Antero Mäntyranta (Winter Olympics 1960–1972; winning seven medals at three of them) had a variant in the erythropoietin receptor that enhanced red blood cell production resulting in very high total body hemoglobin and VO2max which together with high training volume and talent for the sport have contributed to his astonishing achievements. In this context, it seems reasonable to propose that any reductionist search for factors that explain inter-individual variability in VO2max and how it responds to training or other conditions is likely to interact with these critical physiological pathways. Physiological adaptations of importance for improving VO2max Regular exercise, particularly endurance training (ET), is associated with manifold phenotypic modifications potentially influencing VO2max (Hawley et al., 2014, Hellsten and Nyberg, 2015). These are conventionally systematized into two broader categories according This article is protected by copyright. All rights reserved. to their primary role in the oxygen (O2) transport and utilization chain: enhancing convective O2 delivery or O2 extraction. The former mainly comprise increases in blood volume (BV), Accepted Article O2-carrying capacity of the blood and cardiac output; the latter generally includes skeletal muscle adaptations such as augmented capillarization and mitochondrial content (Kjellberg et al., 1949a, Hoppeler and Weibel, 1998). Adaptations related to muscle motor recruitment were theorized but recently refuted to govern VO2max (Hawkins et al., 2007, Brink-Elfegoun et al., 2007), thus they are not covered in this review, which as a matter of fact aligns with and expands upon the ‘classical’ view of VO2max as being primarily limited by the circulatory capacity to deliver O2 to working muscle (Hill and Lupton, 1923, Bassett and Howley, 1997, Levine, 2008). The reader is referred to a comprehensive review by Levine (Levine, 2008) and recent debates discussing theories and facts for VO2max limitation (Wagner, 2015, Lundby and Montero, 2015). Dissecting the relative roles of training adaptations in determining VO2max improvements is a fundamental topic in exercise physiology with tangible impact on exercise prescription targeting cardiorespiratory fitness (Mezzani and Guazzi, 2016). What follows hereunder is an integration of studies assessing the effects of ET on potential determinants of and their impact upon VO2max in untrained but otherwise healthy humans. Nearly half a century ago, the question arose whether the increase in VO2max following ET is underlain by adaptations characterized by ‘central’ and/or ‘peripheral’ nature, respectively and primarily reflected by the 2 components of the Fick equation (Figure 2): maximal cardiac output (Qmax) and arteriovenous O2 difference (a-vO2diff) (Ekblom et al., 1968, Saltin et al., 1968). These early studies reported an increase in Qmax alone or along with a-vO2diff following 8-16 weeks of ET in few (< 10) healthy young individuals (Ekblom et al., 1968, Saltin et al., 1968). Subsequent studies also had small sample sizes but confirmed prevalent increases in Qmax with variable avO2diff in response to diverse ET interventions ranging from 5 to 52 weeks of duration, in mainly untrained individuals accross all ages (Klausen et al., 1982, Spina et al., 1992, Beere et al., 1999b, Helgerud et al., 2007, Murias et al., 2010b, Weng et al., 2013, Bonne et al., 2014, Jacobs et al., 2013, Macpherson et al., 2011, Wang et al., 2014b, Ehsani et al., 1991, Fujimoto et al., 2010, Haennel et al., 1989, Hijazi et al., 1998, Marshall et al., 2001, Morris et al., 2002, Murias et al., 2010a, Spina et al., 1993a, Spina et al., 1993b, Spina et al., 1998, Wang et al., 2014a). Pooled evidence suggests that with training interventions lasting ≥ 12 weeks the effects on a-vO2diff become evident (Montero et al., 2015d, Montero and Diaz- Canestro, 2015). Importantly, these meta-analyses reveal a linear relationship between This article is protected by copyright. All rights reserved. VO2max and Qmax but not a-vO2diff increases (Montero et al., 2015d, Montero and DiazCanestro, 2015). This highlights the predominant dependence of any improvement in VO2max Accepted Article induced by ET on Qmax, concurring with the classic view of VO2max being basically determined by the capacity of the cardiovascular system to deliver O2 (Levine, 2008, Taylor et al., 1955). With the Fick equation in mind, the first point at issue is to understand which adaptations explain ET-induced increases in Qmax and how these specifically contribute to VO2max. This is illustrated in Figure 2. In this regard, experimental studies have demonstrated that increases in Qmax and VO2max following 6 weeks of ET are reverted to pre training levels after negating training-induced gains in BV by means of phlebotomy (Montero et al., 2015b, Bonne et al., 2014). This strongly suggests that early increases in Qmax and VO2max are exclusively dependent on BV. Enhanced BV is thought to augment the pressure gradient from central venous reservoir to right atrium leading to enhanced venous return, cardiac preload and stroke volume via the Frank-Starling mechanism (Hopper et al., 1988, Coyle et al., 1986, Convertino et al., 1991, Kanstrup and Ekblom, 1982). Of note, any BV-mediated increase in Qmax has little influence on O2 delivery and thereby VO2max if only plasma volume (PV), but not also the total red blood cell volume (RBCV) is augmented, since the O2 carrying capacity of the blood is diminished (Montero et al., 2015c, Warburton et al., 2000, Keiser et al., 2015). BV expansion induced by ET commonly comprises ~10 % increments in PV following a single exercise bout and levelling off after approximatly 2 weeks, along with similar or lower increments in RBCV noted after 6 to 12 weeks (Convertino, 2007, Sawka et al., 2000, Bonne et al., 2014, Helgerud et al., 2007, Warburton et al., 2004, Montero et al., 2015b). With longer-term ET, PV, RBCV and absolute hemoglobin mass have been shown substantially enhanced (up to 40 %) in endurance athletes (Dill et al., 1974, Brotherhood et al., 1975, Heinicke et al., 2001, Lundby and Robach, 2015). In these, donation of 1 unit of blood (450 ml) immediately prompts an 8 % decrease in VO2max, which is not re-established after 1 week (Panebianco et al., 1995). Endurance athletes also present cardiac eccentric hyperthropy, largely increased left ventricular compliance and reduced total peripheral vascular resistance (i.e., decreased afterload), all potentially facilitating higher stroke volume (Spence et al., 2011, Levine et al., 1991, Fleg et al., 1994). Similar cardiac adaptations but of lesser magnitude are observed after 6-12 months of ET in previously untrained individuals, although their independent contribution to Qmax remains to be experimentally elucidated (Arbab-Zadeh et al., 2014, This article is protected by copyright. All rights reserved. Spence et al., 2011). Whilst speculative, cardiac adaptations might be partially the consequence of chronically elevated BV and central venous pressure (CVP) (Convertino et Accepted Article al., 1991), independently of direct ET effects. Taken together, it can be unequivocally concluded that increases in BV along with total oxygen-carrying capacity, as essentially characterized by RBCV expansion, are fundamental for improving VO2max. Despite the preponderant influence of RBCV on VO2max, there is some uncertainty regarding the mechanisms stimulating erythropoiesis with ET. Acute (normoxic) exercise transiently activates hypoxia inducible factor-2α in and erythropoietin (EPO) release from contracting skeletal muscle (Lundby et al., 2006a, Rundqvist et al., 2009). Plasma EPO concentration seems unaffected up to 48 h following 60 min of whole-body (running, cycling) exercise (Bodary et al., 1999, Schmidt et al., 1991). In contrast, up to ~100 % increments in circulating EPO levels have been reported immediately (Robach et al., 2014) (Schwandt et al., 1991) and 2-3 days after (Robach et al., 2014, Schwandt et al., 1991, Roecker et al., 2006) prolonged strenuous exercise ((ultra)marathon), although this is not a universal finding (Weight et al., 1992). These observations could be confounded by concurrent changes in PV. In addition, it has been proposed that the rapid increase in PV in the first few days of ET might impel the erythropoietic system to approach a new equilibrium in that haematocrit is partially restored to pre training levels (Jelkmann and Lundby, 2011, Sawka et al., 2000, Schmidt and Prommer, 2008). Yet, there is no proof that augmented PV per se stimulates erythropoietin (EPO) synthesis in the setting of normal RBCV. Moreover, the observation of slightly higher increases in RBCV than PV after 6 weeks of ET suggests that RBCV expansion might be, at least in part, not ultimately regulated by PV (Montero et al., 2015b). Alternatively to hypoxia-related signals, the filling state of (and/or blood volume distribution in) the cardiovascular system, as reflected by CVP, is markedly reduced during several hours after whole-body exercise (Kirsch et al., 1975, Kirsch et al., 1986). This is detected by venoatrial and central arterial stretch receptors that stimulate the secretion of BV-regulating hormones possibly contributing to the erythropoietic response (Montero et al., 2016). When CVP is acutely decreased by whole-body tilting, plasma EPO concentration increases, an effect mediated by concomitant increases in vasopressin, which may enhance EPO secretion through the activation of V1a receptors (Engel and Pagel, 1995, Montero et al., 2016). Thus, ET-induced erythropoiesis might well be independently regulated by parallel endocrine feedback loops to those regulating PV and interstitial fluid homeostasis. Furthermore, ET improves the hematopoietic microenvironment and alters the secretion pattern of This article is protected by copyright. All rights reserved. catecholamines, peptides (growth hormone, insulin-like growth factor) and steroid hormones (testosterone, cortisol), all of which may influence red blood cell production and/or release Accepted Article from the bone marrow (Hu and Lin, 2012). The relative importance of the above mechanisms in the erythropoietic response to ET remains elusive and a compelling challenge for understanding the physiological bases of aerobic conditioning. Importantly, common variants in genetic pathways that might modulate key physiological pathways controlling convective O2 delivery have not been identified yet (Sarzynski et al., 2016). However, at least on case report of a rare variant in a champion athlete associated with a very high RBCV reinforces the crucial point raised herein (Thompson, 2012). The contribution of adaptations associated with peripheral adaptations and associated O2 extraction to VO2max improvements merits attention. As previously mentioned, a-vO2diff is found to be primarily increased with long-term ET, although phenotypic modifications typically considered to enhance O2 extraction emerge in the early stages of ET (Montero et al., 2015b). Herein, large increments in skeletal muscle capillarization (18 %) and mitochondrial volume density (43 %) are observed after 6 weeks of ET but a-vO2diff is unaltered (Montero et al., 2015b). In line with this, VO2max is not improved with 4-7 weeks of one-legged ET when Qmax is not increased, even if maximal O2 extraction is enhanced in the trained versus control leg (Gleser, 1973, Rud et al., 2012). Indeed, muscle O2 extraction is not maximal at VO2max and recent experimental studies demonstrate a twofold functional reserve in untrained individuals (Calbet et al., 2015). One clever series of experiments in rats provides further insight into this fundamental question. Davies and colleagues (Davies et al., 1982) studied iron-depleted animals who were anemic and lacked normal mitochondrial function in their skeletal muscles. These animals had reduced values for VO2max and endurance running time. Acute correction of their anemia normalized their VO2max values but had little impact on their endurance running time. This model confirms the primacy of convective O2 transport as the major determinant of VO2max. In parallel with these observations are observations that in individuals who have been training for many years, mitochondrial adaptations are uniformly high but dissociated from VO2max (Lundby and Jacobs, 2016). In this line, in healthy humans mitochondrial oxidative capacity exceeds that of O2 delivery at VO2max and hence is currently not considered to limit O2 extraction (Boushel et al., 2011, Lundby and Montero, 2015). Collectively considered, within-muscle adaptations enhancing maximal O2 extraction may therefore not be crucial for increasing a-vO2diff and thereby VO2max. In contrast to our conclusions, opposite This article is protected by copyright. All rights reserved. viewpoints mainly based on theoretical models are available (Wagner, 1992, Wagner, 2015, Accepted Article Lundby and Montero, 2015). O2 extraction (as measured) and a-vO2diff may be functions of the distribution of blood flow among active/inactive muscle fibers and other tissues at distinct levels (whole-body, limb, muscle) (Kalliokoski et al., 2005, Kalliokoski et al., 2001, Calbet et al., 2006a). Blood flow distribution (BFD) during exercise is plausibly determined by the interplay of vascular dilator/constrictor function, sympathetic drive and microvascular structure (Calbet et al., 2006a, Lundby et al., 2008, Emerson and Segal, 1997, Joyner and Casey, 2015). A change in BFD could explain the observation that some individuals exhibit no change in leg a-vO2diff but increased whole-body a-vO2diff after 12 weeks of ET with cycle ergometry (Beere et al., 1999a). Moreover, BFD is improved and a-vO2diff augmented in leg exercising muscle (quadriceps femoris) during submaximal exercise in chronically trained individuals (Kalliokoski et al., 2001). Regardless, the fact that a-vO2diff is near peak levels at exhaustion in un- and trained individuals precludes a major impact on VO2max of any potential improvement in BFD during (sub)maximal exercise (Lundby et al., 2006b, Rud et al., 2012). Non-responders to exercise training: our concerns. In recent years much attention has been given to the emerging concept that some individuals seemingly do not respond to endurance exercise training with a marked improvement in VO2max. These individuals have accordingly been termed non-responders. Considering the immense health benefits associated with cardiorespiratory fitness and improvements in VO2max, and the general relationship between fitness and all-cause mortality, it is possible that such findings may lead certain individuals to refrain from exercise training due to uncertain benefits and even what some have called adverse responses to training for selected risk factors (Bouchard et al., 2012). In this context we are also concerned that the underlying scientific evidence for the non-responder phenomenon has underappreciated limitations, and that a hypothesis neutral search for DNA variants that determine responses to training is unlikely to yield explanations that can be reconciled with known physiological principles related to oxygen transport and gas exchange that we have outlined above. We are also concerned that the non-responder concept fails to acknowledge the protective effects of exercise that go beyond changes in traditional risk factors associated with the endurance trained state (Joyner and Green, 2009). This article is protected by copyright. All rights reserved. Where did the non-responder concept come from? Accepted Article The term non-responders was coined based on data gathered from the Heritage Family Study. In this landmark study 483 sedentary individuals as part of family groups were assigned to 20 weeks of exercise training three times a week. Initially they trained for 30 min at a heart rate corresponding to 55% of their VO2max, but every two weeks the intensity and duration was progressively increased until they exercised 50 min at 75% of VO2max. This was achieved in training week 14. The range of improvements in VO2max varied from zero to more than 1l O2.min-1 (Bouchard et al., 2011, Skinner et al., 2001). Subsequent retrospective analysis suggested that up to 49% of the variation in the response to training could be ascribed to heredity based on the cumulative presence or absence of 21 single nucleotide polymorphisms. These results are however based on stepwise regression procedures thoroughly discredited in the literature and thus should be interpreted with caution (Mundry and Nunn, 2009). Additionally, the number of gene variants that might be associated with increased VO2max is increasing in number and as of 2009 “The human gene map for performance and healthrelated fitness phenotypes” included 239 genes (Bray et al., 2009). However most of these variants or pathways are not clearly linked to the physiological systems responsible for the bulk transport of oxygen from air to tissues that dominate the physiological determinants of VO2max and almost all have very small effect sizes. In this context, the Heritage author’s have acknowledged that candidate gene and genome wide linkage studies have failed to clearly contribute to our understanding of the molecular basis for variations in exercise adaptations (Sarzynski et al., 2016). It is also interesting to note that variants of the angiotensin converting enzyme gene once thought to be associated with very high levels of VO2max were not confirmed when a large sample of elite endurance athletes were studied (Rankinen et al., 2000). We highlight this finding because it shows that even for a gene that might plausibly play a role the regulation of blood volume and/or cardiac hypertrophy a clear story about DNA variants and VO2max is hard to come by. An often ignored or overlooked finding from the Heritage study is that exercise intensity was automatically controlled by heart rate monitoring. This may have caused training workloads to be gradually reduced over the course of a training session as heart rate drifts upwards with continuous exercise. Indeed, fluctuations in training workload did occur and partly explained the training response (Sarzynski et al., 2016). While not specifically reported, the nonresponders might reasonably be the individuals with the greatest mis-match between target and achieved workloads, which would beg the obvious question: Did the non-responders This article is protected by copyright. All rights reserved. simply not respond to the training regime as the intensity and/or volume was too little? It should also be noted that smaller studies in a number of cohorts including identical twins Accepted Article (Prud'homme et al., 1984) showed highly variable changes in VO2 max in response to what might be described as the adult fitness style training outlined above for the Heritage study. Finally, while it is easy to be critical of Heritage in retrospect, it should be remembered that this was an absolutely state of the art study when it was developed and required a truly impressive degree of coordination and intellectual insight to design and execute it also included women along with several racial groups and a range of age. That a clear pattern of DNA variants did not emerge to explain a high percentage of the Heritage findings likely represent limitations that have emerged subsequently in what has been termed the “common variant” hypothesis which was widely anticipated at the time the study was conceived (Shields, 2011, Weiss, 2008). Will all previously untrained individuals gain from exercise training if pushed sufficiently? At the turn of the last century (e.g. 1900) it was suggested that exercise training facilitates VO2max in humans and that both volume and intensity may influence the outcome hereof. Soon after and based on experiences of athletes and coaches high intensity repetition, fartlek and interval training was widely adopted and revolutionized running performances. Two of the most notable athletes to employ such approaches into their training regimes were Roger Bannister (first person under 4:00 min for the Mile) and Emil Zatopek (Multiple Olympic). Some of the earliest scientific studies of athletes who used high intensity training showed that with even modest volumes of high intensity training very high VO2max values could be achieved (Robinson et al., 1937). Additionally, early work from a number of labs provided evidence that these high values for VO2max were associated with evidence for very large stroke volumes and total body hemoglobin (Kjellberg et al., 1949a, Kjellberg et al., 1949b) Since then a myriad of scientific studies have demonstrated that interval training is effective in increasing VO2max. For example, after two months of intense interval training (15 sec maximum running/ 15 sec rest in the end totaling 15 min of high intensity exercise or 3 min maximum running/ 3 min rest, again performed so that total time of high intensity exercise = 15 min) conducted three times per week (i.e. same as in the Heritage study) “all subjects (n=37) demonstrated increases in this (VO2max) functional capacity” (Figures 2 and 3 in (Knuttgen et al., 1973)). Later Hickson and co-workers (Hickson et al., 1977) found that a 10 This article is protected by copyright. All rights reserved. week long training intervention alternating between daily (6/week) interval (5 × 5 min at VO2max) and continuous (as fast as possible for 30-40 min) running improved VO2max by at Accepted Article least 700 ml O2.min-1 in all (n=8) participants. These training regimes are obviously of much more rigorous nature than that applied in the Heritage Family Study and one could be tempted to conclude along the lines of the conventional no pain – no gain wisdom. It can also be argued however that not many individuals, and perhaps especially untrained individuals will be willing to endure such trainings. The studies do however suggest that with the right training that non-responders to exercise training do not exist. In further support, a recent meta-analysis (Bacon et al., 2013) revealed that interval/high intensity training improves VO2max slightly greater than those typically reported with “adult fitness based continuous training” despite many of the interval studies were of shorter duration and with fewer training sessions per week. Ross and colleagues (Ross et al., 2015) performed a much needed study demonstrating the importance of exercise intensity and volume in regards to VO2max improvements. In that study 192 individuals were assigned to 24 weeks of training consisting of 5 sessions/week including either A) 180/300 kcal (female/male) conducted at 50% of VO2peak, B) 360/600 kcal conducted at 50% or C) 360/600 kcal conducted at 75%. In groups A and B 38.5 and 17.6%, respectively, of the participants were classified as non-responders after the training intervention, whereas the number was 0 in group C. This study thus demonstrates that when doubling training volume (group A vs B) then non-responders are decreased by 50%, and if more intensity is added to that (group B vs C) then the phenomenon entirely disappear. Based on this study it could be speculated that if the participants in the Heritage study had trained 5 sessions per week rather than 3, then perhaps the outcome may have been entirely different. How should one then train to avoid ending up as a non-responder? Nordesjö (Nordesjö, 1974) published similar improvements in VO2max (with improvements noted in all participants) between groups running either A) 15 min once per week at a heart rate (HR) of 190 beats.min-1, B) 3 × 60 min runs/week at a HR of 150 or C) 5 × 120 min runs/week at HR of 110. Thus an obvious tradeoff between intensity and volume exists, and it seems likely that if the training intensity had been higher in the low intensity group (Group A) in the study by Ross (Ross et al., 2015) and also in the Heritage study then the rate of non-responders would be minimal or non-existent. There are also number anecdotal observations (Astrand and Rodahl, 1986) on “average” young men who have subjected themselves to prolonged and intense almost professional style training and achieved VO2 max values of nearly 60 ml.kg- This article is protected by copyright. All rights reserved. 1 .min-1. While this value seems high at first gland imagine a young man with a VO2max of 3.2 l.min-1 and body weight of 80 kg. Such an individual would almost certainly be able to Accepted Article increase his max to roughly 4 l.min-1 with several years of training. If at the same time his body weight dropped to 70 kg his VO2max would equal 57 ml.kg-1.min-1. By no means elite, but a value sufficient perhaps to run a marathon in just over three hours. Such values certainly do not seem inconceivable based on the original study by Hickson and colleagues and more recent studies by Howden and colleagues (Howden et al., 2015). In the later study it was surprisingly demonstrated that females respond somewhat less to a training intervention as compared to males. The very small number of participants in that study (7 males and 5 females) urges for more studies on this topic including greater subject numbers and the concomitant assessment of hemoglobin mass. Furthermore, it is very important to determine iron status of the included females as ~20% may be anemic and hence likely less prone to expand their hemoglobin mass. Additionally, much of the data we have focused on was obtained from studies in men because only limited numbers of women were studied before the 1990s or 2000s. Finally, will any genetic markers associated with responses to short term adult fitness training be replicated in response to more prolonged and intense endurance training? Conclusion and perspective We are of the opinion that overwhelming data exists demonstrating that all previously untrained humans will respond to endurance exercise training regimes provided the stimulus is sufficient. These improvements are for the greatest part associated with improvements in RBCV observed within weeks, leading to higher O2 carrying capacity, stroke volume and hence O2 transport capacity. Surprisingly little is known regarding the mechanisms facilitating the expansion of RBCV with exercise training. With months of training, stroke volume could also be facilitated by cardiac growth and moderately increased ventricular compliance. Considering that factors facilitating VO2max with endurance training are largely limited to the expansion of RBCV and stroke volume, it might make sense for studies aiming to predict or explain the biological mechanisms responsible for variations in VO2max trainability should: 1) use a training program designed to elicit maximum increases in VO2max within a given individual. This means that prolonged and intense training will be required, and 2) focus on hormonal responses, gene variants and molecular adaptations of relevance for This article is protected by copyright. All rights reserved. the dominant physiological pathways we have emphasized in this paper. From an evolutionary perspective, when DNA variants are found in specific populations (such as Accepted Article groups that have been exposed for many generations to profound hypoxia), there is substantial evidence for selection and relatively common variants in key physiological pathways emerge (Simonson, 2015). In this context, the estimated VO2max values for male hunter gatherers are on the order of 55-60 ml.kg-1.min-1 (Joyner and Casey, 2015). Since these values are similar to those attainable by most lean active young males, we question – in the absence of a clear argument and evidence for selection pressure - whether easily identifiable DNA variants in the key physiological pathways for VO2max we have outlined will be identified for both average individuals and also elite endurance athletes. Conflict of Interest: The authors have no conflict of interests to declare. References. Arbab-Zadeh, A., Perhonen, M., Howden, E., Peshock, R. M., Zhang, R., Adams-Huet, B., Haykowsky, M. 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Some of these data points are previously published (Montero et al., 2015a, Lundby and Robach, 2015). All data were obtained within the “Lundby lab” by means of CO (red blood cell volume) and inert gas (cardiac output) re-breathing. Figure 2. Physiological adaptations underlying improvements in maximal oxygen uptake (VO2max) with exercise training Expansion of plasma volume is observed within hours following whole-body exercise and remains elevated with regular exercise training (Convertino, 2007, Sawka et al., 2000, Bonne et al., 2014, Helgerud et al., 2007, Warburton et al., 2004, Montero et al., 2015b). Increases in red cell blood volume and total oxygen-carrying capacity ensue after few weeks of training (Montero et al., 2015b, Bonne et al., 2014). The resultant augmentation of blood volume facilitates venous return leading to higher end-diastolic volume and stroke volume (SV) via the Frank-Starling mechanism (Hopper et al., 1988, Coyle et al., 1986, Convertino et al., 1991, Kanstrup and Ekblom, 1982). Changes in plasma and red blood cell volumes will also affect the a-vO2diff. Months of training may result in cardiac eccentric hyperthropy, moderately enhanced ventricular compliance and reduced afterload, possibly facilitating higher end-diastolic volume (Spence et al., 2011, Levine et al., 1991, Fleg et al., 1994). Maximal heart rate (HR) is commonly not affected by exercise training. Skeletal muscles adaptations potentially contributing to O2 extraction and thereby arteriovenous oxygen difference (a-vO2diff) mainly include increases in mitochondrial volume density/oxidative capacity and capillarization. These are clearly noticed in the early weeks of training but have no influence a-vO2diff (Montero et al., 2015b), plausibly attributable to the twofold functional This article is protected by copyright. All rights reserved. reserve in muscle O2 extraction at VO2max in the untrained state (Calbet et al., 2015). Enhanced a-vO2diff is evident following approximately 12 weeks of training (Beere et al., Accepted Article 1999a, Montero and Diaz-Canestro, 2015, Montero et al., 2015b). This could be due to improved blood flow distribution primarily determined by combined adaptations in vascular dilator/constrictor function and microvascular structure (Calbet et al., 2006a, Lundby et al., 2008, Emerson and Segal, 1997). Ultimately, there is little ‘room’ for increasing a-vO2diff and thus VO2max improvements are essentially determined by increases in SV along with relatively preserved oxygen-carrying capacity of the blood. This article is protected by copyright. All rights reserved. Accepted Article This article is protected by copyright. All rights reserved.
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