Acta Physiol 2017, 220, 218–228

REVIEW
Biology of VO2max: looking under the physiology lamp

C. Lundby,1 D. Montero2 and M. Joyner3

1 Z€urich Center for Integrative Human Physiology, Institute of Physiology, University of Z€urich, Z€urich, Switzerland
2 Department of Cardiology, University Hospital Z€urich, Z€urich, Switzerland
3 Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA

Received 12 July 2016, Abstract

revision requested 26 August
2016,
revision received 28 October
2016,
accepted 28 October 2016
Correspondence: C. Lundby,
Institute of Physiology, University
of Z€urich, Winterthurerstrasse
190, CH-8057 Z€urich,
Switzerland.
E-mail: carsten.lundby@uzh.ch
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 interindividual variability: (i) 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 gen-
eral concepts are also informed by cross-sectional studies in athletes that
have very high values for VO2max. Therefore, (ii) variations in VO2max
improvements with exercise training are also likely related to variations in
these physiological determinants. (iii) 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.
Keywords exercise, genetics, mitochondria, non-responders, performance,
red blood cell volume.

our position. In the street lamp parable, an intoxi-

Physiology, reductionism and street lamps
Maximal oxygen uptake (VO2max) and its closely
related clinical correlate cardiorespiratory fitness are
key determinants of both elite performance in endur-
ance sports and mortality in the general population
(Pedersen & Saltin 2015). In this review, we argue the
dominant and deterministic physiological pathways
that account for a vast majority of interindividual
variability in VO2max are well known and centre on
total body haemoglobin 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
interindividual variability in VO2max and its response
to training should focus on these physiological path-
ways. We adapt the ‘street lamp parable’ to highlight
cated 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 caution-
ary tale about observational bias. By contrast, in the
case of VO2max, failure to focus where the physiolog-
ical light has led to limited insight into any DNA vari-
ants and other molecular mechanisms 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
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 pro-
longed and intense training. The other type of study is
the classic short-term intervention in ‘average’ citizens

218 © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12827
Acta Physiol 2017, 220, 218–228
that seeks to understand the phenotypic changes asso-
ciated with periods of exercise training lasting a few
months.
Red cell mass, total body haemoglobin, 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 manoeuvres 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 domi-
nate 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 physio-
logical 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 M€antyranta (Winter
Olympics 1960–1972; winning seven medals at three
of them) had a variant in the erythropoietin recep-
tor that enhanced red blood cell production resulting
in very high total body haemoglobin 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 interindividual 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
Figure 1 Correlations between VO2max,
maximal cardiac output (a) and red
blood cell volume (b). Some of these
data points are previously published
(Lundby & Robach 2015, Montero
et al. 2015a). All data were obtained
within the ‘Lundby lab’ by means of CO
(red blood cell volume) and inert gas
(cardiac output) re-breathing.
© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12827
C Lundby et al. · Trainability of humans
potentially influencing VO2max (Hawley et al. 2014,
Hellsten & Nyberg 2015). These are conventionally
systematized into two broader categories according to
their primary role in the oxygen (O2) transport and
utilization chain: enhancing convective O2 delivery or
O2 extraction. The former mainly comprises increases
in blood volume (BV), O2-carrying capacity of the
blood and cardiac output; the latter generally includes
skeletal muscle adaptations such as augmented capil-
larization and mitochondrial content (Kjellberg et al.
1949a, Hoppeler & Weibel 1998). Adaptations
related to muscle motor recruitment were theorized
but recently refuted to govern VO2max (Brink-Elfegoun
et al. 2007, Hawkins 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 & Lupton
1923, Bassett & 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 (Lundby & Montero
2015, Wagner 2015).
Dissecting the relative roles of training adaptations
in determining VO2max improvements is a fundamen-
tal topic in exercise physiology with tangible impact
on exercise prescription targeting cardiorespiratory fit-
ness (Mezzani & Guazzi 2016). What follows hereun-
der 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 two components of the Fick equa-
tion (Fig. 2): maximal cardiac output (Qmax) and arte-
riovenous 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 fol-
lowing eight to 16 weeks of ET in few (<10) healthy
young individuals (Ekblom et al. 1968, Saltin et al.
219
Trainability of humans · C Lundby et al. Acta Physiol 2017, 220, 218–228

VO2max = SV x HR x (a - vO2 diff)

+ - + - -
MONTHS
Ejection fraction

+ +
Ventricular
compliance End-diastolic Cardiac Better Muscle
+ volume afterload distribution O2% extraction
Ventricular of blood to
dimensions active fibres
+ + ? ?
Venous + +
MONTHS return Mitocondrial
Vascular Capillarity
function volume density
+ and oxidative
Blood + capacity
volume

+ WEEKS WEEKS WEEKS

Plasma Red blood
volume cell volume

DAYS WEEKS

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 exer-
cise training (Bonne et al. 2014, Convertino 2007, Helgerud et al. 2007, Montero et al., 2015a, Sawka et al. 2000, Warbur-
ton et al. 2004). Increases in red cell blood volume and total oxygen-carrying capacity ensue after few weeks of training
(Bonne et al. 2014, Montero et al., 2015a). The resultant augmentation of blood volume facilitates venous return leading to
higher end-diastolic volume and stroke volume (SV) via the Frank-Starling mechanism (Kanstrup & Ekblom 1982, Coyle
et al. 1986, Hopper et al. 1988, Convertino et al. 1991). 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 (Levine et al. 1991, Fleg et al. 1994, Spence et al. 2011).
Maximal heart rate (HR) is commonly not affected by exercise training. Skeletal muscle 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., 2015a), plausibly attributable to the twofold functional reserve in muscle O2 extraction at VO2max
in the untrained state (Calbet et al. 2015). Enhanced a-vO2diff is evident following approx. 12 weeks of training (Beere et al.
1999, Montero & Dıaz-Ca~nestro, 2016, Montero et al., 2015a). This could be due to improved blood flow distribution pri-
marily determined by combined adaptations in vascular dilator/constrictor function and microvascular structure (Emerson &
Segal 1997, Calbet et al. 2006a, Lundby et al. 2008). 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.

1968). Subsequent studies also had small sample sizes
but confirmed prevalent increases in Qmax with vari-
able a-vO2diff in response to diverse ET interventions
ranging from five to 52 weeks of duration, in mainly
untrained individuals across all ages (Klausen et al.
1982, Haennel et al. 1989, Ehsani et al. 1991, Spina
et al. 1992, 1993a,b, 1998, Hijazi et al. 1998, Beere
et al., 1999, Marshall et al. 2001, Morris et al. 2002,
Helgerud et al. 2007, Fujimoto et al. 2010, Murias
et al. 2010a,b, Macpherson et al. 2011, Jacobs et al.
2013, Weng et al. 2013, Bonne et al. 2014, Wang
et al. 2014). Pooled evidence suggests that with train-
ing interventions lasting ≥12 weeks, the effects on a-
vO2diff become evident (Montero & Dıaz-Ca~ nestro,

220 © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12827
Acta Physiol 2017, 220, 218–228
2016, Montero et al. 2015b). Importantly, these
meta-analyses reveal a linear relationship between
VO2max and Qmax but not a-vO2diff increases (Mon-
tero & Dıaz-Ca~ nestro, 2016, Montero et al. 2015b).
This highlights the predominant dependence of any
improvement in VO2max induced by ET on Qmax, con-
curring with the classic view of VO2max being basi-
cally determined by the capacity of the cardiovascular
system to deliver O2 (Taylor et al. 1955, Levine
2008).
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
(Bonne et al. 2014, Montero et al., 2015a). 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 (Kanstrup
& Ekblom 1982, Coyle et al. 1986, Hopper et al.
1988, Convertino et al. 1991). 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, because the O2-carrying capac-
ity of the blood is diminished (Warburton et al. 2000,
Keiser et al. 2015, Montero et al. 2015a). BV expan-
sion induced by ET commonly comprises ~10% incre-
ments in PV following a single exercise bout and
levelling off after approx. 2 weeks, along with similar
or lower increments in RBCV noted after six to
12 weeks (Sawka et al. 2000, Warburton et al. 2004,
Convertino 2007, Helgerud et al. 2007, Bonne et al.
2014, Montero et al., 2015a). With longer term ET,
PV, RBCV and absolute haemoglobin mass have been
shown substantially enhanced (up to 40%) in endur-
ance athletes (Dill et al. 1974, Brotherhood et al.
1975, Heinicke et al. 2001, Lundby & Robach 2015).
In these, donation of 1 unit of blood (450 mL) imme-
diately 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 compli-
ance and reduced total peripheral vascular resistance
(i.e. decreased afterload), all potentially facilitating
higher stroke volume (Levine et al. 1991, Fleg et al.
1994, Spence et al. 2011). Similar cardiac adaptations
but of lesser magnitude are observed after six to
© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12827
C Lundby et al. · Trainability of humans
12 months of ET in previously untrained individuals,
although their independent contribution to Qmax
remains to be experimentally elucidated (Spence et al.
2011, Arbab-Zadeh et al. 2014). While speculative,
cardiac adaptations might be partially the consequence
of chronically elevated BV and central venous pressure
(CVP) (Convertino et al. 1991), independently of
direct ET effects, taken together, it can be unequivo-
cally 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 mech-
anisms stimulating erythropoiesis with ET. Acute (nor-
moxic) exercise transiently activates hypoxia inducible
factor-2a 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 (Schmidt et al.
1991, Bodary et al. 1999). 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 (Schwandt et al. 1991,
Roecker et al. 2006, Robach et al. 2014) 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
that might impel the erythropoietic system to
approach a new equilibrium in that haematocrit is
partially restored to pre-training levels (Sawka et al.
2000, Schmidt & Prommer 2008, Jelkmann &
Lundby 2011). Yet, there is no proof that augmented
PV per se stimulates erythropoietin (EPO) synthesis in
the setting of normal RBCV. Moreover, the observa-
tion 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., 2015a).
Alternatively to hypoxia-related signals, the filling
state of (and/or blood volume distribution in) the car-
diovascular system, as reflected by CVP, is markedly
reduced during several hours after whole-body exer-
cise (Kirsch et al. 1975, 1986). This is detected by
veno-atrial 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 &
221
Trainability of humans · C Lundby et al.
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 homoeostasis. Fur-
thermore, ET improves the hematopoietic microenvi-
ronment and alters the secretion pattern of
catecholamines, peptides (growth hormone, insulin-
like growth factor) and steroid hormones (testos-
terone, cortisol), all of which may influence red blood
cell production and/or release from the bone marrow
(Hu & 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 con-
ditioning. Importantly, common variants in genetic
pathways that might modulate key physiological path-
ways 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., 2015a).
Herein, large increments in skeletal muscle capillariza-
tion (18%) and mitochondrial volume density (43%)
are observed after 6 weeks of ET, but a-vO2diff is
unaltered (Montero et al., 2015a). 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 vs. 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 which were anaemic and lacked nor-
mal mitochondrial function in their skeletal muscles.
These animals had reduced values for VO2max and
endurance running time. Acute correction of their
anaemia normalized their VO2max values but had lit-
tle impact on their endurance running time. This
model confirms the primacy of convective O2 trans-
port as the major determinant of VO2max. In parallel
with these observations are observations that in indi-
viduals who have been training for many years, mito-
chondrial adaptations are uniformly high but
dissociated from VO2max (Lundby & Jacobs 2016). In
this line, in healthy humans, mitochondrial oxidative
222 © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12827
Acta Physiol 2017, 220, 218–228
capacity exceeds that of O2 delivery at VO2max and
hence is currently not considered to limit O2 extrac-
tion (Boushel et al. 2011, Lundby & Montero 2015).
Collectively considered, within-muscle adaptations
enhancing maximal O2 extraction may therefore not
be crucial for increasing a-vO2diff and thereby VO2-
max. In contrast to our conclusions, opposite view-
points mainly based on theoretical models are
available (Wagner 1992, 2015, Lundby & Montero
2015).
O2 extraction (as measured) and a-vO2diff may be
functions of the distribution of blood flow among
active/inactive muscle fibres and other tissues at dis-
tinct levels (whole-body, limb, muscle) (Kalliokoski
et al. 2001, 2005, Calbet et al. 2006a). Blood flow
distribution (BFD) during exercise is plausibly deter-
mined by the interplay of vascular dilator/constrictor
function, sympathetic drive and microvascular struc-
ture (Emerson & Segal 1997, Calbet et al. 2006a,
Lundby et al. 2008, Joyner & Casey 2015). A change
in BFD could explain the observation that some indi-
viduals exhibit no change in leg a-vO2diff but
increased whole-body a-vO2diff after 12 weeks of ET
with cycle ergometry (Beere et al. 1999). Moreover,
BFD is improved and a-vO2diff augmented in leg exer-
cising 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 individu-
als precludes a major impact on VO2max of any poten-
tial 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. Consid-
ering the immense health benefits associated with car-
diorespiratory 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 train-
ing 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 evi-
dence for the non-responder phenomenon has under-
appreciated 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
Acta Physiol 2017, 220, 218–228
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 tradi-
tional risk factors associated with the endurance
trained state (Joyner & Green 2009).
Where did the non-responder concept come
from?
The term non-responders was coined based on data
gathered from the Heritage Family Study. In this land-
mark study, 483 sedentary individuals as part of fam-
ily 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 2 weeks, the intensity and dura-
tion were 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 1 L O2 min 1
(Skinner et al. 2001, Bouchard et al. 2011). Subse-
quent 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 regres-
sion procedures thoroughly discredited in the litera-
ture and thus should be interpreted with caution
(Mundry & 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 health-related
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 determi-
nants of VO2max and almost all have very small
effect sizes. In this context, the Heritage authors have
acknowledged that candidate gene and genomewide
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 find-
ing because it shows that even for a gene that might
plausibly play a role in 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
© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12827
C Lundby et al. · Trainability of humans
automatically controlled by heart rate monitoring.
This may have caused training workloads to be gradu-
ally 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 non-
responders might reasonably be the individuals with
the greatest mismatch between target and achieved
workloads, which would beg the obvious question:
Did the non-responders simply not respond to the
training regimen 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
(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 which 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 represents 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 (Weiss 2008, Shields
2011).
Will all previously untrained individuals gain
from exercise training if pushed sufficiently?
At the turn of the last century (e.g. 1900), it was sug-
gested that exercise training facilitates VO2max in
humans and that both volume and intensity may influ-
ence the outcome hereof. Soon after and based on
experiences of athletes and coaches, high-intensity rep-
etition, fartlek and interval training were widely
adopted and revolutionized running performances.
Two of the most notable athletes to employ such
approaches into their training regimens 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 vol-
umes of high-intensity training, very high VO2max
values could be achieved (Robinson et al. 1937).
Additionally, early work from a number of laborato-
ries provided evidence that these high values for
VO2max were associated with evidence for very large
stroke volumes and total body haemoglobin (Kjellberg
et al. 1949a,b).
223
Trainability of humans · C Lundby et al.
Since then, a myriad of scientific studies have
demonstrated that interval training is effective in
increasing VO2max. For example, after 2 months of
intense interval training (15-s maximum running/15-s
rest in the end totalling 15 min of high-intensity exer-
cise or 3-min maximum running/3-min rest, again per-
formed 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’ (Figs 2 and 3 in the study by
Knuttgen et al. (1973)). Later Hickson and co-work-
ers (Hickson et al. 1977) found that a ten-week-long
training intervention alternating between daily (six per
week) interval (5 9 5 min at VO2max) and continu-
ous (as fast as possible for 30–40 min) running
improved VO2max by at least 700 mL O2 min 1 in
all (n = 8) participants. These training regimens 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 conven-
tional no pain – no gain wisdom. It can also be
argued, however, that not many individuals, and per-
haps especially untrained individuals, will be willing
to endure such trainings. The studies do, however,
suggest that with the right training, that non-respon-
ders to exercise training do not exist. In further sup-
port, 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
that many of the interval studies were of shorter dura-
tion and with fewer training sessions per week. Ross
and colleagues (Ross et al. 2015) performed a much
needed study demonstrating the importance of exer-
cise intensity and volume in regard to VO2max
improvements. In that study, 192 individuals were
assigned to 24 weeks of training consisting of five ses-
sions per week including either (A) 180/300 kcal (fe-
male/male) conducted at 50% of VO2peak, (B) 360/
600 kcal conducted at 50% or (C) 360/600 kcal con-
ducted 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 demon-
strates that when doubling training volume (group A
vs. B), non-responders are decreased by 50%, and if
more intensity is added to that (group B vs. C), then
the phenomenon entirely disappears. Based on this
study, it could be speculated that if the participants in
the Heritage study had trained five sessions per week
rather than three, then perhaps the outcome may have
been entirely different.
How should one then train to avoid ending up as a
non-responder? Nordesj€ o (Nordesj€o 1974) published
224 © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12827
Acta Physiol 2017, 220, 218–228
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 9 60 min runs per week at
a HR of 150 or (C) 5 9 120 min runs per week at
HR of 110. Thus, an obvious trade-off between inten-
sity 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 a number of anecdotal observations
(Astrand & 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 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 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 sur-
prisingly demonstrated that females respond some-
what less to a training intervention as compared to
males. The very small number of participants in that
study (seven males and five females) urges for more
studies on this topic including greater subject numbers
and the concomitant assessment of haemoglobin mass.
Furthermore, it is very important to determine iron
status of the included females as ~20% may be anae-
mic and hence likely less prone to expand their hae-
moglobin mass. Additionally, much of the data we
have focused on were 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 pro-
longed and intense endurance training?
Conclusion and perspective
We are of the opinion that overwhelming data exist
demonstrating that all previously untrained humans
will respond to endurance exercise training regimens
provided the stimulus is sufficient. These improve-
ments are for the greatest part associated with
improvements in RBCV observed within weeks, lead-
ing to higher O2-carrying capacity, stroke volume and
hence O2 transport capacity. Surprisingly, little is
Acta Physiol 2017, 220, 218–228
known regarding the mechanisms facilitating the
expansion of RBCV with exercise training. With
months of training, stroke volume could also be facili-
tated by cardiac growth and moderately increased
ventricular compliance. Considering that factors facili-
tating VO2max with endurance training are largely lim-
ited 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 (i) use a
training programme designed to elicit maximum
increases in VO2max within a given individual. This
means that prolonged and intense training will be
required and (ii) focus on hormonal responses, gene
variants and molecular adaptations of relevance for
the dominant physiological pathways we have empha-
sized in this paper. From an evolutionary perspective,
when DNA variants are found in specific populations
(such as groups that have been exposed for many gen-
erations 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 & Casey 2015). Because
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 pres-
sure – whether easily identifiable DNA variants in the
key physiological pathways for VO2max we have out-
lined will be identified for both average individuals
and also elite endurance athletes.
Conflict of interest
The authors have no conflict of interests to declare.
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