PERSPECTIVE FOR PROGRESS

Concepts About V̇O2max and Trainability Are

Context Dependent
Michael J. Joyner1 and Carsten Lundby2
1
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN; and 2Center for Physical
Downloaded from https://journals.lww.com/acsm-essr by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3YiN3qTGLcvKn/eg8lC4RD3Merb5PDCYDtm4RmNi6hNfmFKXusagweg== on 08/09/2018

Activity Research, University Hospital of Copenhagen, Denmark

JOYNER, M.J. and C. LUNDBY. Concepts about V ˙O

2max and trainability are context dependent. Exerc. Sport Sci. Rev., Vol. 46,
No. 3, pp. 138–143, 2018. Some individuals show little or no increase in maximal oxygen consumption (V̇O2max) in response to training
programs consistent with public health guidelines. However, results from studies using more intense programs challenge the concept that
some humans have limited trainability. We explore the implications of these divergent observations on the biology of trainability and propose
a new set of twin studies to explore them. Key Words: exercise, cardiorespiratory fitness, gene variants, twins, trainability

always uniform over time. So an initial slow or fast response

Key Points
• Trainability may depend on the training stimulus or dose
of exercise.
• The gene variants associated with V̇O2max trainability iden-
tified to date are remote from key physiological pathways in
the O2 transport system like stroke volume and total body
hemoglobin.
• We suggest a multidose exercise training study in twins
might be able to help resolve a number of conceptual issues
related to trainability and the exercise dose-response dura-
tion relation for V̇O2max.
INTRODUCTION
Anyone who has ever spent much time in a gym or at sports
practice will tell you that the rate at which a given individual
within a group “gets in shape” or acquires new skills in response
to training can vary dramatically. Trainability is the general term
used to describe either the rate of change or the magnitude of
change in fitness or skill in response to training. An individual
who shows rapid and marked improvement to a given “dose” of
training is said to be highly trainable. A slower responder or an
individual who improves less over time is said to be less train-
able. However, the rate of change to a training stimulus is not
Address for correspondence: Michael J Joyner, M.D., FACSM, Department of
Anesthesiology and Perioperative Medicine Mayo Clinic, Rochester, MN
55905 (E-mail: joyner.michael@mayo.edu).
Accepted for publication: April 6, 2018.
Editor: Demetra D. Christou, Ph.D.
0091-6331/4603/138–143
Exercise and Sport Sciences Reviews
DOI: 10.1249/JES.0000000000000150
Copyright © 2018 by the American College of Sports Medicine
may not always be predictive of the total magnitude of the re-
sponse after a period of months or longer. In addition, because
the duration of a vast majority of training studies is measured
in months, it is not clear how years of training might influence
ideas about trainability and nonresponders.
It also is important to distinguish trainability from intrinsic
(or “natural”) ability. Some individuals might enter a training
program faster, stronger, or more skilled than others. However,
high levels of initial fitness are generally unrelated to the mag-
nitude of change seen in response to standard training pro-
grams. In the case of endurance or strength-related sports, it
also is possible that those who perform well on either laboratory
or field tests with minimal formal training might simply have
been more active during other facets of life. For example, in
sedentary middle-aged obese individuals, there is a strong posi-
tive correlation between the intensity of incidental physical ac-
tivity and maximal oxygen consumption (V̇O2max) (1).
However, there are clearly inherent biological factors related
to oxygen transport or muscular strength that are independent
of physical activity. Thus, in terms of baseline fitness in free-liv-
ing humans, it can be difficult to discern the role of intrinsic bi-
ological factors from acquired responses to the activities of daily
living. There is speculation, for example, that average baseline
V̇O2max in untrained subjects is typically higher in cultures
where active transportation via cycling is more common.
In the context of these comments, trainability for the purposes of
this article will be defined as the increase in V̇O2max in response to
a specific training program. However, we recognize the limita-
tions of this definition because there are many potential exer-
cise training dose-response and duration interactions possible
for a given individual. Thus, the determination of trainability
for a given individual in most studies is a snapshot based on
his or her response to a specific program. The concept of train-
ability also might be better served if more attention were paid to
the range of values observed in a cohort in response to a specific

138

Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
program versus a more narrow focus on nonresponders to pro-
grams based on current physical activity guidelines.
In some studies, cardiorespiratory fitness (CRF) is reported.
This measure is frequently used in large population studies of fit-
ness and health or mortality when graded exercise testing with-
out direct measurements of gas exchange has been performed.
Although CRF and V̇O2max are highly correlated, CRF is esti-
mated from peak METs levels and expressed as metabolic
equivalents or METs. Each MET equaling 3.5 ml−1·kg−1·min−1
(e.g., resting metabolic rate), with increments of this unit being
used to describe CRF. For example, CRF in an individual with
a V̇O2max of 35 ml−1·kg−1·min−1 would equal 10 METs. In these
cases, equations are used to link peak workload with a “MET
equivalent.” There also are validated questionnaire-based ap-
proaches that can be used (2). Because CRF and V̇O2max are
highly correlated, and because we are interested in the biology
of oxygen transport, the remainder of the article focuses on
V̇O2max.
Trainability and Why it Matters
Beyond its obvious importance to coaches and individuals
interested in talent identification for sport, trainability has po-
tential individual and public health implications. This is espe-
cially true for V̇O2max. The reasoning goes something like
this: fitness is a powerful predictor of all-cause and cardiovascu-
lar mortality, and endurance exercise training is recommended
to improve cardiovascular fitness. In population studies, each
1-MET (3.5 ml−1·kg−1·min−1) increase in V̇O2max is associated
with a roughly 15% reduction in all-cause mortality (3). Impor-
tantly, such an increase in V̇O2max is generally viewed as
achievable by most humans with modest levels of training.
In this context, if there are individuals who do not respond to
training with an increase in V̇O2max, then do they receive a
mortality benefit from training? Do such individuals need a dif-
ferent training program? Are the current physical activity and
exercise guidelines sufficient to ensure most people who follow
them increase their fitness? Finally, high levels of fitness may be
more protective against cardiovascular and all-cause mortality
than physical activity (4,5).
The aforementioned questions also highlight the contrasts
and potential overlap between the terms training and physical
activity. Although exercise training is a structured program de-
signed to improve physical capacity, there also can be adaptive
responses to incidental, leisure time, or occupational physical
activity. As previously noted, individuals who engage in more
Figure 1. Idealized relation between (A) cardiac output and (B) hemoglobin (Hb) mass with maximal oxygen consumption (V̇O2max). Figure based on data
from (8,9).
Volume 46 • Number 3 • July 2018
Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
high-intensity incidental physical activity have higher V̇O2max
values (1). In this context, an advantage of measuring re-
sponses to training versus estimates of other forms of physical
activity is that better quantification and control of the input
(training) stimulus is possible.
Before delving into the physiological and biological determi-
nants of V̇O2max and trainability, it is important to note that
some of the epidemiological and outcomes literature on exercise
relate fitness to health or mortality outcomes, whereas other
studies relate measures of physical activity to outcomes. As
discussed earlier, there is some overlap in these variables; in
general fitness is more protective than physical activity (3–5).
In either case, the protection afforded by either high levels of
CRF or physical activity are generally greater than might be pre-
dicted based on their effects on traditional risk factors like hy-
pertension, diabetes, and blood lipids when compared with
drug therapy (3,6).
In summary, trainability is important when considering the
relation between V̇O2max and health outcomes. Because some
individuals show bigger changes in V̇O2max in response to train-
ing, these variable responses raise questions about how uniform
the health benefits of training are. They also raise questions
about the extent to which health benefits are related to in-
creases in V̇O2max and improvements in other risk factors
linked to health outcomes.
Determinants of V̇O2max
V̇O2max describes the maximum ability of a whole organism
to transport oxygen from the air to the tissues and especially
the exercising skeletal muscles (7). It is thus dependent on
and potentially limited by numerous sites in the so-called O2
transport cascade. This cascade includes the following: 1) pul-
monary ventilation, 2) diffusion of oxygen across the pulmo-
nary capillary membrane to the blood, 3) the bulk “flux” of
O2 away from the lungs via a combination of cardiac output
and arterial O2 content, 4) increased blood flow to contracting
muscles, and 5) diffusion of O2 from blood to tissue and ulti-
mately oxidative metabolism in the mitochondria.
Although each of the five factors previously outlined can in-
fluence V̇O2max, in large groups of healthy humans with a 2- to
3-fold range in V̇O2max, peak or maximum cardiac output and
total body hemoglobin mass seem to predominate as determi-
nants of V̇O2max (Fig. 1). The other factors only become poten-
tially rate limiting in either specific patient groups and in some
cases (e.g., pulmonary ventilation), elite endurance athletes (8).
V̇O2max and Trainability 139
Training Program
Current public health guidelines typically recommend adults
engage in 150–300 min·wk−1 of moderate to vigorous aerobic
physical activity, with lesser amounts suggested for those engag-
ing in more vigorous exercise (10). When large numbers of pre-
viously untrained healthy young and middle-aged humans
engage in guideline-based training for 10–20 wk, the increase
in V̇O2max ranges from 0 to approximately 40%–60% (11–13)
with average values of around 15%–20% usually reported and
higher mean increases (approximately 25%–30%) seen with
more frequent or intense training (11,14). Importantly, the in-
crease in V̇O2max with training is not related to baseline
V̇O2max and is not influenced by race, sex, or age (up to middle
age) (12,13). In this context, the iconic HERITAGE study
reported that roughly 10%–20% of subjects responded only
minimally to training with an increase in V̇O2max and thus
demonstrated limited or no trainability in response to a pub-
lic health guideline-informed program (12,13).
Along similar lines, when the effects of such guideline-based
training programs on blood pressure, blood lipids, and blood
glucose are evaluated, roughly 10%–30% of subjects show no
improvement or perhaps a worsening of values (15). However,
the risk factor adverse responder concept has been challenged
on a number of grounds (16). In addition, many of the protective
effects of fitness and physical activity on health likely operate
via mechanisms not captured via traditional risk factors (6).
In contrast to guideline-based training programs, studies that
have used more intense levels of exercise have typically shown
that the vast majority of young healthy subjects are trainable
(14). In addition, one of us (see Montero and Lundby) recently
showed that when healthy young men performed intense cycle
training 4 or 5 d·wk−1, all of the studied subjects showed an in-
crease in V̇O2max (11). By contrast, some subjects who were
only training 1, 2, or 3 d·wk−1 showed limited trainability.
However, when two additional training sessions per week were
added to the limited-trainability subjects, they all became train-
able. In this study, trainability was defined as an increase greater
than the typical measurement error for maximal attained
Figure 2. Summary figure showing that nonresponders to training 1, 2, or
3 d·wk−1 became responders when additional training was added. Figure
based on data from (11). The notation +2 indicates that two additional train-
ing days were added.
140 Exercise and Sport Sciences Reviews
Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
workload. This is the only study where individual study partic-
ipant “improvements” versus “no-improvements” is based on an
objective measure. Figure 2 shows key data from this study. It
also seems that all subjects in training studies using repeated in-
tervals of 3–5 min at exercise intensities greater than 90% of
V̇O2max show an increase in V̇O2max (17). Finally, only a few
studies have followed people during prolonged periods, and
Howden et al. (18) found that with 1 yr of high-volume training
that included high-intensity exercise, male subjects responded
with 22% increases in V̇O2max, whereas the number was 15%
for female participants. In addition, this increase was somewhat
higher than that observed by Scharhag-Rosenberger et al. (19)
(average 16%, range 9%–20%), who followed subjects over the
course of 1 yr of guideline-based (3 d·wk−1) training.
A key question that arises when guideline-based studies are
compared with studies using more rigorous training programs
is the effect on the range of V̇O2max responses. Is the range of
responses similar but shifted to a higher value? Does the range
increase, or conversely, does the range decrease? The limited
data available on this topic suggest that the range of responses
may be similar but shifted to a higher value (14). However,
these data do not provide information about whether a non
(or limited) responder to training also would show a limited
response to a more rigorous or perhaps longer duration pro-
gram. In terms of training volume, it can however be seen from
Figure 2 that the most extreme responses (21%, 25%, and 24%)
observed when training 1, 2, and 3 times per week, respectively,
become the norm when training 4 (26%) or 5 (32%) times per
week. Hence, comparing studies applying different training fre-
quencies, intensities, and durations may be of limited utility.
Our discussion of the divergent results seen in response to dif-
fering training programs and the questions raised by this discus-
sion highlight a number of related ambiguities in the current
data and thinking on this topic: First, have reports of V̇O2max
nonresponders to specific training programs been the focus of
too much attention? Do nonresponders primarily represent
the tail of a distribution of responses to a given dose of exercise
applied for a given duration? Second, consistent with our use of
the word context in the title of this article, uncertainty in the
trainability and nonresponder discussion also can arise based
on technical errors in the measurement of V̇O2max and also
day-to-day variability in human biology and motivation. These
potential confounds need clear definition when discussing the
results of a given study, comparing results between studies,
and when considering the topic as a whole. Third, clear metrics
related to subject adherence to any program are critical. Fourth,
there also are potential issues about the scaling of V̇O2max
values that need to be considered. In general, we favor liters
per minute but this is not ironclad, and there are numerous scal-
ing issues that might need to be considered depending on the
size and body composition range of the subjects involved
(20). Fifth and finally, will the nature of the distribution of
V̇O2max responses to training change if the dose and duration
of exercise is changed?
Even the most demanding training programs used in con-
trolled studies pale in comparison to the hours per day of train-
ing that elite athletes do for years (21). If this sort of elite
training represents a near maximal dose applied for years, would
all individuals exposed to it show marked increases in V̇O2max
and would the distribution of responses be expanded or
www.acsm-essr.org
compressed? Our hypothesis is that a maximal dose exercise
stimulus applied for a long duration would result in marked
training responses in essentially all humans and compress the
range of responses. However, we fully acknowledge that this
proposition is likely “not testable” via a randomized controlled
trial.
Subject Characteristics
As mentioned previously, in young and middle-aged popula-
tions, sex and age do not seem to influence trainability in re-
sponse to a guideline-based program, and this also includes
both white and black subjects. However, there is little informa-
tion about sex and age influences on trainability in response to
more rigorous programs. This is especially true in adults aged 60
or older. There are some data (low subject number) suggesting
that in response to 1 yr of rigorous training, cardiac hypertrophy
is less in young women than men (18). There also are some data
to suggest the loss of female reproductive hormones at meno-
pause might influence training responses (22). Aging and sex
differences are clearly areas that are ripe for additional studies
on trainability that include a range of long-term programs with
varying degrees of frequency, intensity and duration.
Biological Factors — Genetics
Data from a limited number of studies on twins indicate that
V̇O2max values in the untrained state and the response to train-
ing are markedly influenced by genetics (23–25). Likewise,
HERITAGE used a family study design to show that approxi-
mately 47% of the increase in V̇O2max to training was heritable
(12,13). The HERITAGE team subsequently identified a num-
ber of genetic markers and developed a retrospective genetic
panel based on 21 SNP gene variants that predicted approxi-
mately 50% of the training response among individuals (26).
However, several observations challenge the idea that ge-
netic factors are the major determinant of trainability. First,
we have argued that none of the gene variants identified in
HERITAGE are clearly linked to cardiac output, stroke vol-
ume, blood volume, and red cell mass — the predominant phys-
iological determinants of V̇O2max (7,8). In addition, a survey of
approximately 3000 elite male endurance athletes who regu-
larly compete at the international level has identified no com-
mon variants associated with unusually high V̇O2max values in
these men (27). Of note, it seems reasonable to assume that
these men’s training is likely sufficient to generate maximum bi-
ological adaptations in their O2 transport systems.
In contrast, a rare variant in at least one Olympic champion
skier has been associated with high red cell mass and hemoglo-
bin values have been associated with a very high V̇O2max
value (28). In addition, both blood doping and exogenous
erythropoietin (EPO) administration can increase V̇O2max in
both trained and untrained subjects (9,29,30). The finding
of a rare variant related to EPO in a single outlier human is im-
portant because emerging concepts in genetics research have
argued that such findings can inform the search for more com-
mon variants that might affect the same biological systems. In
this context, it is interesting that common gene variants in
EPO-related signaling pathways have not emerged in studies
of large numbers of elite endurance athletes with high V̇O2max
values (31).
Volume 46 • Number 3 • July 2018
Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
The previous discussion on genetic factors versus the well-
established physiological determinants that explain V̇O2max is
perhaps informed by recent theoretical work on complex traits
(32). This work has advanced the idea that certain “core genes”
or genetic pathways can be major players in a given phenotype
with modifying contributions from many more pathways. The
inability so far to identify specific genes and variants associated
in a major way with the key physiological pathways central to
exercise capacity leads us to question the extent to which this
conceptual model applies to V̇O2max. The standard response
to this critique is that larger sample sizes and more sophisticated
modeling are needed to unravel this problem. A counterre-
sponse is that if no obvious signal is seen in large groups of out-
lier phenotypes, then the odds of such a signal emerging via a
larger sample size in the general population seems low. In either
case, it should be remembered that as late as 2006, at least one
leading proponent of genetic causation (Francis Collins) was
quoted in the Wall Street Journal as suggesting that “… there
are about 12 genes involved [in diabetes], and that all of them
will be discovered in the next two years,” (33). Although this
was not an exercise-specific comment, it highlights the earlier
expectation that a limited number of common variants would
explain complex human phenotypes.
Another response to the argument that the DNA variants re-
ported to date are not linked to the known physiological deter-
minants of V̇O2max is that they may be drivers of adaptability
via regulation of replication, transcription, translation, autoph-
agy, apoptosis, angiogenesis, miRNAs, and other molecular
transducers of the adaptations to the repeated stress of exercise
that in the end impact the determinants of the Fick equation.
In this context, we note that substantial responses to exercise
training still occur in genetic knockouts of PGC1α and other
pathways proposed as master regulators of many exercise re-
sponses (34,35). We interpret these data as highlighting that
the responses to exercise are incredibly redundant with many
potential biological pathways possible to generate a phenotypic
response. Along similar lines, lessons from experimental evolu-
tion studies in model organisms show predicable convergent
phenotypes but unpredictable karyotypes in response to a given
selective pressure. Although perhaps not directly related to
short-term adaptations to exercise training in humans, these ob-
servations are another example of the concept that multiple
pathways to a given phenotype are possible (36).
FUTURE PERSPECTIVES
Back to the Future: Is a Next Wave of Twin
Studies Needed?
So far, we have defined the concept of trainability as it ap-
plies to V̇O2max and we have reviewed why this is important
from both an individual wellness and public health perspective.
For healthy young and middle-aged people, we have concluded
the following: 1) trainability varies among people, 2) if given a
sufficient stimulus, the likelihood of a true nonresponder in
these age groups seems low, 3) it is not known if extremely rig-
orous training over years will alter the range of V̇O2max in-
creases with training or merely shift them upwards, 4) twin
and family studies suggest a significant heritable (genetic) com-
ponent to trainability, 5) the search for genetic explanations
that might explain trainability has not identified key variants
V̇O2max and Trainability 141
Figure 3. Idealized potential results in response to a rigorous program of endurance exercise training on maximal oxygen uptake (V̇O2max) in monozygotic
(MZ; open oval) and dizygotic (DZ; shaded oval) twins. Panel A shows that that the correlation between V̇O2max in untrained MZ twin pairs is “tighter” compared
with DZ twins. Panel B shows the effects of training on V̇O2max if genetic factors play a dominant role in the response. Under these circumstances, there is in-
creased convergence of V̇O2max in the MZ twins and increased divergence in the DZ twins. The range of V̇O2max values also increases in both groups, with some
individuals and pairs showing limited trainability. Panel C shows the effects of training on V̇O2max if factors related to training stimulus play a dominant role in the
response. Under these circumstances, there is increased convergence of V̇O2max in both groups of twins. The range of V̇O2max values also decreases in both
groups, with all individuals and pairs showing evidence of marked trainability.

that intersect in a clear-cut way with the deterministic physio-
logical pathways. In addition to these five main points, there
are issues like sex differences and aging that might further con-
found concepts related to trainability, not to mention specific
disease states.
When we consider the aforementioned five main points, it
seems to us they can be collapsed into three central questions
that could be addressed in comprehensive studies on mono
and dizygotic twins: first, will rigorous training reduce the vari-
ability in V̇O2max observed between untrained dizygotic twins
(24,25)? Second, in dizygotic twins, will rigorous training in-
crease the correlation in V̇O2max between twin A and twin B
so that it is similar to the more uniform V̇O2max values seen in
monozygotic twins (23–25)? Third, will rigorous training in ei-
ther dizygotic or monozygotic twins expand or reduce the range
of increases in V̇O2max seen among groups of twins? In this con-
text, it is important to note that the most informative aerobic
exercise training study on twins that focused on V̇O2max was
conducted in monozygotic twins, and we would like to see an in-
tervention that included evaluation of expanded dose-response-
duration relation in both mono and dizygotic twins (23).
A simple experimental design might include a period of
10 wk of guideline-based training and outcome measurements
followed by 10 wk of a rigorous program similar to that
pioneered by Hickson (37) in the late 1970s. In addition to
V̇O2max, key outcome variables might include changes in stroke
volume and cardiac size along with red cell mass. In addition,
the interpretation of such data is likely to be straightforward.
If the responses to our three questions converge in mono and di-
zygotic twins after rigorous training, we would argue that train-
ability can be more about the training stimulus than genetic
factors in response to high-dose training. If the responses diverge,
then the role of genetic factors as determinants of trainability
would be emphasized. Figures 3A–C show idealized results dem-
onstrating these possible categories of outcomes.
An obvious limitation to our paradigm is that it will be
“small-N” and thus unlikely to shed light on any specific gene
variants or pathways that might play a role in trainability. How-
ever, our paradigm will provide fundamental insights into the
concepts related to trainability and its biological basis. It also
will provide an important interventional study that will test
the primacy of the physiological pathways that are largely seen
as deterministic for V̇O2max. If the findings from our hypothet-
ical study were to show increased heritability estimates for
V̇O2max (and also cardiac output and red cell volume as key
contributors to trainability), then a case to continue to search
for additional gene variants and complex networks that might
explain trainability would be strengthened. If the findings sug-
gest that the training stimulus per se is a more critical factor,
then perhaps reductionist searches for gene variants related to
trainability and V̇O2max might be deemphasized.
References
1. McGuire KA, Ross R. Incidental physical activity is positively associated
with cardiorespiratory fitness. Med. Sci. Sports Exerc. 2011; 43(11):2189–94.
2. Nes BM, Janszky I, Vatten LJ, Nilsen TI, Aspenes ST, Wisløff U. Estimating
V̇O2peak from a nonexercise prediction model: the HUNT Study, Norway.
Med. Sci. Sports Exerc. 2011; 43(11):2024–30.
3. Ross R, Blair SN, Arena R, et al. Importance of Assessing Cardiorespiratory
Fitness in Clinical Practice: A Case for Fitness as a Clinical Vital Sign:
A Scientific Statement From the American Heart Association. Circulation.
2016; 134(24):e653–99.
4. Lavie CJ, Arena R, Swift DL, et al. Exercise and the cardiovascular system:
clinical science and cardiovascular outcomes. Circ. Res. 2015; 117(2):
207–19.
5. DeFina LF, Haskell WL, Willis BL, et al. Physical activity versus cardiore-
spiratory fitness: two (partly) distinct components of cardiovascular health?
Prog. Cardiovasc. Dis. 2015; 57(4):324–9.
6. Joyner MJ, Green DJ. Exercise protects the cardiovascular system: effects be-
yond traditional risk factors. J. Physiol. 2009; 587(Pt 23):5551–8.
7. Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to
muscles during exercise: a hierarchy of competing physiological needs.
Physiol. Rev. 2015; 95(2):549–601.
8. Lundby C, Montero D, Joyner M. Biology of V̇O2max: looking under the
physiology lamp. Acta. Physiol. (Oxf.). 2017; 220(2):218–28.
9. Lundby C, Robach P, Saltin B. The evolving science of detection of 'blood
doping'. Br. J. Pharmacol. 2012; 165(5):1306–15.

142 Exercise and Sport Sciences Reviews www.acsm-essr.org

Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
10. CDC. Current physical activity guidelines CDC 2008. Available at: https://
www.cdc.gov/cancer/dcpc/prevention/policies_practices/physical_activity/
guidelines.htm. Accessed April 6, 2018.
11. Montero D, Lundby C. Refuting the myth of non-response to exercise train-
ing: 'non-responders' do respond to higher dose of training. J. Physiol. 2017;
595(11):3377–87.
12. Bouchard C, An P, Rice T, et al. Familial aggregation of V̇O2max response
to exercise training: results from the HERITAGE Family Study. J. Appl.
Physiol. (1985). 1999; 87(3):1003–8.
13. Skinner JS, Jaskólski A, Jaskólska A, et al. Age, sex, race, initial fitness, and
response to training: the HERITAGE Family Study. J. Appl. Physiol.
(1985). 2001; 90(5):1770–6.
14. Ross R, de Lannoy L, Stotz PJ. Separate effects of intensity and amount of
exercise on interindividual cardiorespiratory fitness response. Mayo Clin.
Proc. 2015; 90(11):1506–14.
15. Bouchard C, Blair SN, Church TS, et al. Adverse metabolic response
to regular exercise: is it a rare or common occurrence? PLoS One.
2012; 7(5):e37887.
16. Leifer ES, Mikus CR, Karavirta L, et al. Adverse cardiovascular response
to aerobic exercise training: is this a concern? Med. Sci. Sports Exerc. 2016;
48(1):20–5.
17. Bacon AP, Carter RE, Ogle EA, Joyner MJ. V̇O2max trainability and
high intensity interval training in humans: a meta-analysis. PLoS One.
2013; 8(9):e73182.
18. Howden EJ, Perhonen M, Peshock RM, et al. Females have a blunted car-
diovascular response to one year of intensive supervised endurance training.
J. Appl. Physiol. 2015; 119(1):37–46.
19. Scharhag-Rosenberger F, Meyer T, Walitzek S, Kindermann W. Time
course of changes in endurance capacity: a 1-yr training study. Med. Sci.
Sports Exerc. 2009; 41(5):1130–7.
20. Jensen K, Johansen L, Secher NH. Influence of body mass on maximal
oxygen uptake: effect of sample size. Eur. J. Appl. Physiol. 2001; 84(3):
201–5.
21. Tonnessen E, Sylta O, Haugen TA, Hem E, Svendsen IS, Seiler S. The road
to gold: training and peaking characteristics in the year prior to a gold medal
endurance performance. PLoS One. 2014; 9(7):e101796.
22. Spina RJ, Ogawa T, Kohrt WM, Martin WH 3rd, Holloszy JO, Ehsani AA.
Differences in cardiovascular adaptations to endurance exercise training
between older men and women. J. Appl. Physiol. 1993; 75(2):849–55.
Volume 46 • Number 3 • July 2018
Copyright © 2018 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
23. Prud'homme D, Bouchard C, Leblanc C, Landry F, Fontaine E. Sensitivity
of maximal aerobic power to training is genotype-dependent. Med. Sci.
Sports Exerc. 1984; 16(5):489–93.
24. Klissouras V. Heritability of adaptive variation. J. Appl. Physiol. 1971; 31(3):
338–44.
25. Klissouras V, Pirnay F, Petit JM. Adaptation to maximal effort: genetics and
age. J. Appl. Physiol. 1973; 35(2):288–93.
26. Bouchard C, Sarzynski MA, Rice TK, et al. Genomic predictors of the max-
imal O2 uptake response to standardized exercise training programs. J. Appl.
Physiol. 2011; 110(5):1160–70.
27. Rankinen T, Fuku N, Wolfarth B, et al. No evidence of a common DNA
variant profile specific to world-class endurance athletes. PLoS One. 2016;
11(1):e0147330.
28. de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin re-
ceptor causes dominantly inherited benign human erythrocytosis. Proc.
Natl. Acad. Sci. U. S. A. 1993; 90(10):4495–9.
29. Ekblom BT. Blood boosting and sport. Baillieres Best Pract. Res. Clin.
Endocrinol. Metab. 2000; 14(1):89–98.
30. Jelkmann W, Lundby C. Blood doping and its detection. Blood. 2011; 118(9):
2395–404.
31. Bomba L, Walter K, Soranzo N. The impact of rare and low-frequency ge-
netic variants in common disease. Genome Biol. 2017; 18(1):77.
32. Boyle EA, Li YI, Pritchard JK. An expanded view of complex traits: from
polygenic to omnigenic. Cell. 2017; 169(7):1177–86.
33. Regalado A. New genetic tools may reveal roots of everyday ills: rapid DNA
tests can search many variations at once; probing obesity, memory. The
Wall Street Journal. Available at: https://www.wsj.com/articles/
SB114497175117125656. Accessed April 6, 2018.
34. Ballmann C, Tang Y, Bush Z, Rowe GC. Adult expression of PGC-1α and -1β
in skeletal muscle is not required for endurance exercise-induced enhancement
of exercise capacity. Am. J. Physiol. Endocrinol. Metab. 2016; 311(6):E928–38.
35. Tanner CB, Madsen SR, Hallowell DM, et al. Mitochondrial and perfor-
mance adaptations to exercise training in mice lacking skeletal muscle
LKB1. Am. J. Physiol. Endocrinol. Metab. 2013; 305(8):E1018–29.
36. Simões P, Fragata I, Seabra SG, et al. Predictable phenotypic, but not kar-
yotypic, evolution of populations with contrasting initial history. Sci. Rep.
2017; 7(1):913.
37. Hickson RC, Bomze HA, Holloszy JO. Linear increase in aerobic power in-
duced by a strenuous program of endurance exercise. J. Appl. Physiol. Respir.
Environ. Exerc. Physiol. 1977; 42(3):372–6.
V̇O2max and Trainability 143