Download Gene–Nutrition Interaction in Human Performance and Exercise

REVIEW ARTICLE
Gene–Nutrition Interaction in Human Performance
and Exercise Response
Amy L. Heck, BA, Cristina S. Barroso, MPh, Margaret E. Callie, BS, and Molly S. Bray, PhD
From the Graduate School of Biomedical Sciences and the Human Genetics Center, School of
Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
Recent advances in human performance research have revealed new insight into the many factors that
influence how an individual responds to exercise training. Response to exercise interventions is often
highly variable among individuals, however, and exercise response may be mediated in large part by
variation in genes and nutrition and by gene– environment interactions. It is well established that the
quality and quantity of nutritional intake play a critical role in response to training and in athletic
performance. The body’s adaptation to exercise is also the result of changes in expression of genes
mediated not only by exercise but by multiple factors, including the interaction between exercise,
components of dietary intake, and genetic variation. This review explores the effects of genetic variation
and gene–nutrition interactions in response to exercise training and athletic performance. Nutrition
2004;20:598 – 602. ©Elsevier Inc. 2004
KEY WORDS: exercise, response, genes, nutrition, interaction
INTRODUCTION
Exercise performance results from the complex interaction among
physiologic, biochemical, and psychological factors, among many
others. Years of research have enhanced our understanding of how
the body responds to exercise training from the level of the whole
human to cellular, subcellular, and molecular mechanisms, and
nutritional intake has been established as a primary factor affecting
human performance. In addition, a growing body of research has
provided support for the notion that response to exercise training
may be influenced by genetic variation. Evidence that DNA sequence variation exists within human populations can be seen in
the variety of sizes, shapes, and faces that can be observed in any
group of individuals. The challenge is to determine how variation
in genes and how the interaction between genes and environments,
such as dietary intake, may influence the variability that is seen in
physiologic changes resulting from exercise. With the completion
of the Human Genome Project, a myriad of approaches has been
used to study the effects of genes and gene– environment interactions on exercise performance. Although the effects of exercise
and nutrition on gene function and expression have been fairly
well studied, how the two influence each other or interact with
genetic variation to produce alterations in exercise outcomes is not
well understood. This review briefly summarizes strategies currently being used to elucidate genetic effects that may influence or
be mediated by physical activity and nutritional intake.
GENETIC FACTORS IN EXERCISE AND PHYSICAL
ACTIVITY
Family-based studies have indicated that the propensity to engage
in physical activity, particularly in the form of organized athletics,
This research was supported by National Institutes of Health grants
DK062148, HL073366, HL074377, and QXI30353.
Correspondence to: Molly S. Bray, PhD, Human Genetics Center, University of Texas Health Science Center, 1200 Hermann Pressler, Houston, TX
77030, USA. E-mail: [email protected]
Nutrition 20:598 – 602, 2004
©Elsevier Inc., 2004. Printed in the United States. All rights reserved.
to some extent may be rooted in our genes. Heritability (the
amount of variation in a trait that can be accounted for by variation
in genes) estimates for physical activity measured by self-report or
by observation range from 0.29 to 0.62, with the wide span in
estimates likely due to differences in the age and type of the
subject samples and in the physical activity assessment instruments.1,2 Gottschaldt3 studied the concordance or similarity of
various mental and physical activity traits in monozygotic twins
over the span of 30 y and found that, although cognitive skills
remained highly concordant throughout a lifetime, physical activity level did not, suggesting that environmental factors rather than
genetic factors are more important in determining an individual’s
propensity to be active in later life. Recently, Maia et al.4 studied
411 Portuguese twins of different zygosity to determine the heritability of the amount and type (sports or leisure) of participation
in physical activity. The researchers estimated that up to 68% of
total variation in sports participation was due to genetic factors in
males and 40% in females.4 Using data from the Quebec Family
Study, maximal heritability was found to be 16% to 25% for
physical activity.5 It is likely that a genetic predisposition for
exercise and physical activity improves athletic performance in
part by influencing an individual to begin sports participation early
in life.
Although family-based research has provided support for the
role of genes in human performance, the identification and detection of genes and gene– environment interactions that influence
exercise performance is difficult due to of a number of factors.
First, the response to exercise training is highly heterogeneous and
can be influenced by multiple components in addition to genetic
factors. Second, several to many genes are likely to influence
performance and response to exercise, each with small to moderate
effects. Third, expression of the genetic variation influencing performance may be context dependent (e.g., a genetic predisposition
for muscle hypertrophy may only be evident after a specific type of
resistance training). Fourth, complex physiologic functions such as
the regulation of blood pressure or vasoconstriction during exercise will have multiple pathways and redundancy to ensure survival of the organism. Many association studies of candidate gene
polymorphisms for exercise performance have been conducted
often with conflicting results due, at least in part, to the context
dependency of the genetic effects. Fifth, genes and environments
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Nutrition Volume 20, Numbers 7/8, 2004
Genes, Nutrition, and Exercise Response
599
TABLE I.
GENES ASSOCIATED WITH ALTERATIONS IN METABOLISM
AFTER EXERCISE
Gene
FIG. 1. Interrelation between nutritional intake, genetic variation, and
exercise. In this diagram, genes and nutritional intake may influence
exercise response directly, jointly, or via their effects on each other. In turn,
exercise can alter gene expression and fuel use.
may act independently and in concert to influence the exercise
outcomes of interest. Figure 1 illustrates the interrelation among
nutritional intake, genetic variation, and exercise. In this diagram,
genes and nutritional intake may influence exercise outcomes
directly, jointly, or via their effects on each other. In turn, exercise
can alter gene expression and fuel use.
GENES FOR HUMAN PERFORMANCE
One of the first genes identified as a putative factor in response to
exercise training was the angiotensin-converting enzyme (ACE)
gene. ACE is part of the renin-angiotensin pathway, and an
insertion/deletion (I/D) polymorphism in intron 16 of the ACE
gene has been well studied for its association to hypertension and
left ventricular hypertrophy in multiple study populations. The
deletion (D) allele has been associated with higher protein activity
level compared with the insertion (I) allele, and the I/D polymorphism accounts for up to 47% of the variation in plasma ACE
levels.6,7 Although many association studies of this gene variant
and exercise-related outcomes have been conducted, there is still
conflicting evidence as to the role the ACE I/D polymorphism
plays in athletic performance. Montgomery et al.8 analyzed genotype at the I/D locus within the ACE gene for association to
exercise response and reported that individuals with one or two I
alleles showed significantly greater duration in repetitive arm
flexion time after exercise training than did D/D homozygotes. The
frequency of the I allele has also been shown to be elevated among
elite Australian rowers, British mountaineers, and elite distance
runners compared with the population at large.8 –10 In addition, the
individuals with one or two I alleles were found to have better
exercise heat tolerance compared with D/D homozygotes.11
Although the I allele has been found with greater frequency
among elite athletes, other studies have indicated that the ACE D
allele is associated with exercised-induced left ventricular hypertrophy in young and middle-age males.12–15 Paradoxical findings
for associations with the ACE I and D alleles may be the result of
genetic effects interacting with specific types of training. The D
allele is associated most strongly in athletes who perform in the
short-duration, power-oriented events, whereas the I allele has
been associated with performance in longer-duration events.16
Other studies, primarily in non-athlete or multiple sport athlete
groups, have reported no association between the ACE I/D polymorphism and cardiovascular changes after exercise training.17,18
Although many other genes have been identified as putative factors in determining exercise response, the ACE gene is one of the few
that has a large body of data accumulated, and the conflicting findings
for this gene exemplify the complexity of genetic studies of physical
Protein
transcription
after
exercise
FAT/CD36
Increase
CPT-1
Increase
PPARG
Decrease
AMPK
Increase
SREBP-1c
Increase
ACC2
Increase
LPL
Increase
ADRB2
Increase
UCP3
Decrease
HKII
Increase
PDH
Increase
GLUT-4
Increase
Function
Enhancement of fat
oxidation
Enhancement of fat
oxidation
Transcriptional
activator
Regulatory role in fatty
acid oxidation and
glucose metabolism
Transcription factor
that regulates lipid
metabolism
Controls the rate of
fatty acid oxidation
and triacylglycerol
storage
Hydrolysis of plasma
triacylglycerols
Stimulates lipolysis
from adipocytes
Uncouple respiration,
releasing heat
Catalyzes the
phosphorylation of
glucose
Regulates rate of
carbohydrate
oxidation
Responsible for
glucose transport
into the cell
Reference
Tunstall et al.25
Tunstall et al.25
Tunstall et al.25
Nielsen et al. 2002
Ikeda et al. 2002.
Schrauwen et al. 2002
Schrauwen et al. 2002
Fujii et al. 1997
Schrauwen et al. 2003
Koval et al.27
Peters 2003
Greiwe et al. 2000
activity and exercise-related outcomes. Table I presents a fraction of
genes that have been shown to influence metabolic response to exercise, and there are countless others that regulate cardiac, respiratory,
and body composition changes after exercise. A recent review of
genes that have been linked to performance phenotypes associated
more than 90 autosomal genes or quantitative trait loci (QTLs), two
X-linked genes, and 14 mitochondrial genes with exercise response or
performance.19
EXERCISE-INDUCED ALTERATIONS IN GENE ACTION
The body’s response to exercise may be regulated at the level of
DNA sequence variation, gene transcription, and/or translation of
proteins. The multitude of changes brought about by a single
exercise bout and by repeated training are the result of activation
of many and varied genes. As with as the study of genetic variation
on exercise outcomes, the effects of short- and long-term exercise
training on gene expression and function are just beginning to be
understood. Gene expression is highly regulated, involving many
proteins and activated by multiple signals. In addition, gene expression and protein assembly are not completely correlated, and
measures of gene expression are merely the first step to understand
the genes’ effect on the cell.
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Heck et al.
It has long been known that an individual who regularly exercises may experience improvements in insulin sensitivity, glucose
metabolism, muscle hypertrophy, changes in mitochondrial content and fiber type of muscle cells, and an increase in the use of fat
as fuel during exercise,20 –22 and expression of numerous genes
associated with these changes has been shown to be induced or
upregulated in exercising skeletal muscle. Richter et al.23 reported
that a single exercise bout can alter glucose transport and insulin
sensitivity in skeletal muscle of rats, and subsequent work has
confirmed these findings in humans.26 Use of specific fuel types
can be enhanced by exercise, and the effect may be short and long
term. Exercise training has been shown to increase basal and
exercise fat oxidation. In a recent study, a single (1-h) bout of
cycle ergometer exercise produced no increase in expression of the
fatty acid transporter (FAT/CD36) or the carnitine palmitoyl
transferase-1 (CPT1) genes, key regulators of fatty acid metabolism; nevertheless, after 9 d of such exercise, expressions of
FAT/CD36 and CPT1 had increased significantly above baseline,
and expression of the peroxisome proliferative activated
receptor-␥ (PPARG) gene, an important factor in adipocyte differentiation, was markedly reduced.24 These findings provide evidence that habitual exercise may specifically improve use of stored
lipids and inhibit the proliferation of adipose tissue.
Gene expression studies often follow discoveries of increased
protein activity after exercise and in many instances shed some
light as to the time course and regulation of these changes. Exercise has been shown to increase translocation of glutamate
transporter-4 (GLUT-4), activities of hexokinase, glycogen synthase, and phosphatidylinositol-3 kinase, and levels of insulin
receptor and insulin receptor substrate-1.25 In healthy subjects
undergoing moderate exercise, hexokinase levels increased after
5 d of physical training; however, increases in insulin sensitivity
and glucose uptake in muscle cells occurred within 24 h, and
mRNA levels of hexokinase II doubled within 3 h after completing
the exercise bout.26 Levels of GLUT-4 mRNA have been shown to
increase in trained subjects over sedentary controls.27 After a
single exercise bout of 60 min on a cycle ergometer at a power
output requiring 73 ⫾ 4% peak oxygen consumption, GLUT-4
gene expression was increased immediately after exercise and
remained significantly higher than baseline 3 h after completion of
the exercise.28
Adenosine monophospate–activated protein kinase (AMPK) is
activated by the rapid decreases in the ratios of adenosine triphosphate to adenosine monophosphate and of phosphocreatine to
creatine in contracting muscle. In this way AMPK is an “energysensing enzyme” and provides a direct link for the exercising state
of the muscle cell with gene transcription. AMPK increases after
exercise29 and activates numerous metabolic genes, such as
GLUT4 and PGC-1, in exercising rodents.30 Two isoforms of
AMPK in humans, AMPK␣-1 and AMPK␣-2, have been shown to
be differentially expressed after the same exercise bout. Low- to
moderate-intensity exercise (40% to 70% of maximum oxygen
capacity) resulted in an increase in the transcription of the
AMPK␣-2 isoform, whereas the AMPK␣-1 isoform was expressed
after maximal sprint exercise in untrained individuals.31 Basal
AMPK␣-1 was increased in response to 4 wk of endurance training, but no such increases were observed in the AMPK␣-2
isoform.31
The genes described above provide a brief glimpse of studies
currently being undertaken to understand the complexity of gene
expression in response to exercise. Gene expression is modified
differentially based on exercise type, intensity, duration, and frequency. In addition, the expression of many genes, such as AMPK,
is dependent on the nutritional status of the individual and, thus,
gene expression studies may be altered by the physiologic state of
the organism being studied. As shown by the number of genes
listed in Table I, further research designed to elucidate the factors
underlying genetic response to exercise is urgently needed.
Nutrition Volume 20, Numbers 7/8, 2004
EXERCISE PERFORMANCE AND NUTRITION
An athlete’s food choices influence that athlete’s biochemical
responses during exercise training, recovery from exercise training, and, most importantly, exercise performance.32 Carbohydrate
(CHO) is a primary source of fuel for the human body, and when
muscle glycogen stores are depleted (e.g., during prolonged exercise) and circulating blood glucose levels are not sufficiently
maintained, exercise intensity and time to exhaustion decrease.33
Consumption of a high-CHO diet in trained individuals results in
increased glycogen storage in skeletal muscle and rapid replenishment of depleted glycogen stores after exercise and has been
shown to increase endurance exercise performance.33–36 In addition, several studies have examined the effects of a high-CHO diet
on metabolic parameters during exercise. Athletes, consuming a
high-CHO, low-fat diet, experienced decreased total fat oxidation
and non-plasma fatty acid oxidation during exercise (for 2 h/d at
70% maximum oxygen capacity) in the fasted state.37 Subjects in
the very low-fat diet group (2% of energy from fat) had lower
intramuscular triacylglycerol stores and higher muscle glycogen
content at rest. Fat oxidation during exercise was reduced by 27%
compared with those who consumed 22% of energy from fat.38
Dietary fat provides a rich source of energy during exercise,
and studies have shown that chronic exposure to high-fat diets
increases use of fat as a fuel source at rest and during exercise.
This is due to an increase in intramuscular triacylglycerol stores
and induction of metabolic genes involved in fat oxidation.39,40
The increase in fat oxidation after exercise results in a decreased
use of stored glycogen for fuel, which may play a role in improving exercise performance. However, muscle and liver glycogen
stores are often lower than in individuals consuming a high-CHO
diet, which may adversely affect exercise performance during
exercise at an intensity of 65% to 85% of maximum oxygen
capacity, when muscle glycogen is thought to play a critical role in
fatigue. Performance outcomes after a high-fat diet can be influenced not only by exercise intensity but also by the duration of the
exercise regime, length of dietary intervention, amount of fat in the
diet, and the type of fat (polyunsaturated, saturated, etc.). Even
with all of the performance variables mentioned above, many
studies have found no improvement in performance after a high-fat
diet.41
The nourishment needs of an athlete depend on the total
amount of daily energy expenditure, type, duration, and frequency
of sport activity, body mass and composition, sex, food preferences, and environmental circumstances.42 Hence, key nutritional
aspects in athletic performance are energy needs, macronutrient
requirements, intake of vitamins and minerals, and hydration.
Similar to the general adult population, energy balance is the
primary nutritional goal for athletes.42 Increased physical activity
augments energy expenditure; hence, athletes have higher than
normal energy requirements. Overall, athletes require sufficient
energy intake to maintain body weight and body composition, and
insufficient energy intake may lead to loss of lean muscle mass,43
loss or failure to gain bone density,44,45 menstrual amenorrhea,46
increased risk of fatigue, injury, and illness,47,48 and diminished
performance.49
NUTRIENT-INDUCED ALTERATIONS IN GENE ACTION
A large body of evidence has determined that macronutrients
(CHO, fats, and proteins) regulate gene transcription. After a
single meal, the body must break down CHO and fat for immediate
energy and for storage. The role of hormones such as insulin in
maintaining homeostasis after a meal has been well characterized,51 as have nutrient-sensing mechanisms that activate appropriate behavioral and metabolic responses after a meal. However,
the immediate regulation of gene expression by CHO, protein, and
fat is not well characterized. The body adapts to differences in
Nutrition Volume 20, Numbers 7/8, 2004
macronutrient intake by regulating genes that play a role in the
breakdown or storage of those nutrients. Hence, fatty acids upregulate genes responsible for their oxidation (removal) or for
adipose differentiation (storage). Macronutrients may affect gene
expression by acting as ligands for transcription factor receptors,
by altering concentrations of substrates or intermediates, or by
affecting signaling pathways.51 Fatty acids induce expression of
aP2, a transcription factor that aids in fatty acid use and storage in
the adipocyte.52,53 Polyunsaturated fatty acids directly stimulate
the production of phosphoenolpyruvate carboxykinase (PEPCK)
mRNA in 3T3-F422A adipocytes, and the induction of this gene is
physiologically relevant because PEPCK is crucial in the formation of triacylglycerols in adipose tissue for storage.54 In addition,
different genes involved in transport of fatty acids into the cell and
mitochondria for use as energy are upregulated by dietary fatty
acids. There are many exhaustive reviews of the effect of fatty acid
intake on gene expression.53,55,56 The mechanisms behind fatty
acid regulation are beyond the scope of this review, but in mammals fatty acids directly activate several transcription factors including peroxisome proliferator-activated receptors (␣, ␤, and ␥),
HNF4-␣, nuclear factor-␬B, and SREBP1c.53
Glucose and products derived from its breakdown can directly
regulate gene expression through gene regions called glucose
response elements and CHO response elements. The gene encoding L-pyruvate kinase contains a glucose response element and is
expressed with glucose activation.57 Pyruvate kinase is a key
enzyme in glycolysis in generating adenosine triphosphate from
the conversion of phospho-enol-pyruvate to pyruvate. Glucose also
influences the activity of transcription factors. Although not as
much is known about CHO regulation of transcription factors as
for fatty acids, it is known that glucose acts on the transcription
factor Sp1 and related family members. Glucose acts by increasing
protein phosphatase-1 activity, which dephosphorylates Sp1, increasing its DNA binding affinity for a number of metabolic genes,
including acetyl COA carboxylase 1 (ACC), leptin, fatty acid
synthase, and adenosine triphosphate citrate-lyase.57 The effect of
CHO on gene expression is important in the context of exercise.
The role of amino acids on gene regulation is currently not very
well understood. Several studies have examined the effects of a
deficiency of certain essential amino acids on gene expression and
found that certain genes are increased in transcription rate in the
absence of key protein components. One such gene is the C/EBP
homologous protein (CHOP), a member of the C/EBP family of
transcription factors. It contains an amino acid response element
that facilitates transcription of the gene in the absence of several
amino acids. The absence of certain amino acids also upregulates
the expression of insulin-like growth factor binding protein-1 and
asparagine synthetase.58
GENE–NUTRITION INTERACTION IN EXERCISE
PERFORMANCE
The interaction of nutrition, genes, and exercise, visually illustrated in Figure 1, is highly complex. Many studies measuring
gene expression in response to exercise control for the effects of
diet, requiring subjects to ingest the same postexercise meal, with
an identical “normalizing diet” for up to 2 wk before the training
experiment.21,26,31,59 In most research designed to determine the
optimum macronutrient content of the athletic diet, researchers
rarely look at gene expression or the molecular mechanism behind
performance benefits that may be seen.40 However, the interaction
among genes, nutrition, and exercise is becoming an active field,
and the remainder of this review outlines recent findings.
After exercise, the muscle works to replenish depleted glycogen through increased glucose uptake, glycogen synthase activity,
and sensitivity to insulin. These changes have been inversely
correlated to muscle glycogen concentration after exercise, and the
Genes, Nutrition, and Exercise Response
601
genes responsible have been demonstrated to increase transcription
after an exercise bout.60 One study tested the hypothesis that
interleukin-6 (IL-6), a cytokine involved in hepatic gluconeogenesis, is altered by diet and exercise. Six male subjects underwent a
dietary intervention of a normal (control) diet or a low-CHO diet
to induce a muscle glycogen level of 60% of those on the normal
diet.61 The day after the initiation of the diet, subjects performed
180 min of two-legged dynamic knee-extensor exercise, and
plasma IL-6 levels were measured before and throughout the
exercise bout. Plasma IL-6 increased in both groups; however,
after 120 min, the low-glycogen group experienced an increase of
two-fold higher than the controls, which remained significantly
higher throughout the exercise. To determine whether this difference was due to increased gene transcription and mRNA levels of
IL-6, muscle biopsies of the vastus lateralis were taken before
exercise and after 30, 90, and 180 min. IL-6 transcription rate and
mRNA content were significantly higher in the low-glycogen
group at 90 and 180 min than in controls.61 This increase in IL-6
expression in response to low glycogen levels is thought to be one
mechanism by which the body regulates muscle glycogen levels, a
key component to endurance performance.
The relation between the amount of glycogen stores brought
about dietary CHO and exercise on gene transcription was also
examined by Pilegaard et al.62 who used cycling exercise to
directly compare the effects of exercise on one leg that had been
depleted of muscle glycogen with one control leg. Glycogen stores
were first built up in both legs by a diet consisting of 500 g of CHO
for 2 d preceding the experiment. Glycogen stores were then
depleted in one leg by one-legged cycling to exhaustion, followed
by 30 min of two-arm cycling exercise to lower liver glycogen
stores the day before the test, with CHO intake restricted until the
beginning of the test. Muscle biopsies were obtained from the
vastus lateralis before the exercise bout, immediately after, and
after 2 and 5 h of recovery. Subjects consumed high-CHO meals
immediately after exercise and at 1 and 3 h of recovery. Muscle
glycogen content was significantly lower at all time points in the
glycogen-depleted leg than in the control leg.62
Before exercise, transcription levels of UCP3, PKD4, HKII,
and LPL genes were similar in the control and low-glycogen legs.
However, only transcription of UCP3 increased significantly after
exercise in the low-glycogen leg. The mRNA levels for PDK4,
HKII, and LPL were significantly higher in the low-glycogen leg
before the exercise; moreover, although exercise did not further
increase these levels, exercise induced increasing mRNA levels to
those similar to the low-glycogen leg, indicating that the genes
could be induced by a change in glycogen content of the muscle
cell.62
In another study, six subjects underwent two trials of twolegged knee-extensor exercise for 3 h at approximately 60% of
their maximum 2-min workload. Muscle glycogen stores were
further depleted in one group by combining exercise to exhaustion
with a low-CHO diet, whereas the control normal muscle glycogen
group ate a high-CHO meal to replenish the muscle glycogen
stores. The time points for muscle biopsies in this study were
pre-exercise, after 1.5 and 3 h of exercise, and after 2 h of
recovery. Transcription of PDK4, HKII, UCP3, and LPL increased
after exercise, but this increase was more dramatic in the lowglycogen group.62 These studies demonstrate that the physiologic
alterations induced by diet and exercise may be manifested at the
molecular level.
CONCLUSIONS
The profound effect of nutrition on exercise performance is well
documented. However, each individual athlete is unique and nutritional requirements depend on age, sex, body size, lean tissue
mass, previous nutritional status, and the duration, frequency,
intensity, and type of physical activity performed. In addition,
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Heck et al.
genetic variation plays a role in response to exercise and human
performance. Completion of the Human Genome Project has provided insight into the role of genetics in performance outcomes.
Similar to other health and disease states such as fitness, longevity
of lifespan, obesity, and diabetes, exercise performance is determined in large part by genetic variation and interactions with
dietary intake. Further, the simultaneous combination of these
factors may have a greater or lesser effect on exercise performance
than either individually. Much research is needed to elucidate the
complex interactions among genes, nutrition, and exercise in influencing physical performance.
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