![Distribution of PPARa 7 intron C allele amongst male and female athletes in two event groups and sedentary controls (EOA endurance-oriented athletes, POA power-oriented athletes). C allele frequencies in endurance-oriented athletes, both men [frequency 11.6% vs controls (frequency 17.1%); P=0.004] and women [frequency 9.0% vs controls (frequency 15.6%); P=0.007] were significantly different. Similarly, C allele frequencies were significantly higher both in male (frequency 26.7%, P=0.0006) and female power-oriented athletes (frequency 28.6%, P= 0.0033) compared to controls](https://www.researchgate.net/profile/Ildus-Ahmetov/publication/226721692/figure/fig1/AS:393673184432145@1470870409421/Distribution-of-PPARa-7-intron-C-allele-amongst-male-and-female-athletes-in-two-event_Q320.jpg)
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ORIGINAL ARTICLE
Ildus I Ahmetov ÆIrina A Mozhayskaya
David M Flavell ÆIrina V Astratenkova
Antonina I Komkova ÆEkaterina V Lyubaeva
Pavel P Tarakin ÆBoris S Shenkman
Anastasia B Vdovina ÆAleksei I Netreba
Daniil V Popov ÆOlga L Vinogradova
Hugh E Montgomery ÆViktor A Rogozkin
PPARagene variation and physical performance in Russian athletes
Accepted: 23 January 2006 / Published online: 28 February 2006
Springer-Verlag 2006
Abstract Peroxisome proliferator-activated receptor a
(PPARa) regulates genes responsible for skeletal and
heart muscle fatty acid oxidation. Previous studies have
shown that the PPARaintron 7 G/C polymorphism was
associated with left ventricular growth in response to
exercise. We speculated that GG homozygotes should be
more prevalent within a group of endurance-oriented
athletes, have normal fatty acid metabolism, and in-
creased percentages of slow-twitch fibers. We have tested
this hypothesis in the study of a mixed cohort of 786
Russian athletes in 13 different sporting disciplines
prospectively stratified by performance (endurance-
oriented athletes, power-oriented athletes and athletes
with mixed endurance/power activity). PPARaintron 7
genotype and allele frequencies were compared to 1,242
controls. We found an increasing linear trend of C allele
with increasing anaerobic component of physical per-
formance (P=0.029). GG genotype frequencies in
endurance-oriented and power-oriented athletes were
80.3 and 50.6%, respectively, and were significantly
(P<0.0001) different compared to controls (70.0%). To
examine the association between PPARagene variant
and fiber type composition, muscle biopsies from m.
vastus lateralis were obtained and analyzed in 40 young
men. GG homozygotes (n=25) had significantly
(P=0.003) higher percentages of slow-twitch fibers
(55.5±2.0 vs 38.5±2.3%) than CC homozygotes (n=4).
In conclusion, PPARaintron 7 G/C polymorphism was
associated with physical performance in Russian ath-
letes, and this may be explained, in part, by the associ-
ation between PPARagenotype and muscle fiber type
composition.
Keywords PPARaÆPolymorphism ÆFatty acids Æ
Muscle fiber type ÆPhysical performance
Introduction
Peroxisome proliferator-activated receptor a(PPARa)is
a transcription factor that regulates lipid, glucose, and
energy homeostasis and controls body weight and vas-
cular inflammation. PPARais expressed at high levels in
tissues that catabolize fatty acids, notably liver, skeletal
muscle, and heart, and at lower levels in other tissues,
including pancreas (Braissant et al. 1996). The level of
expression of PPARais higher in type I (slow-twitch)
than in type II (fast-twitch) muscle fibers (Russel et al.
2003).
Endurance training increases the use of non-plasma
fatty acids and may enhance skeletal muscle oxidative
capacity by PPARaregulation of gene expression
(Russel et al. 2003; Horowitz et al. 2000). PPARareg-
ulates the expression of genes encoding several key
Ildus I Ahmetov (&)ÆI. A Mozhayskaya
Irina V Astratenkova ÆAntonina I Komkova
V. A Rogozkin
Sports Genetics Laboratory, St Petersburg Research Institute
of Physical Culture, 2 Dynamo Street, 197110,
St Petersburg, Russia
E-mail: genoterra@mail.ru
Tel.: +7-812-2371936
Fax: +7-812-2370461
D. M Flavell
Centre for Cardiovascular Genetics, Department of Medicine,
Royal Free and University College London Medical School,
The Rayne Institute, 5 University Street,
WC1E 6JF, London, UK
Ekaterina V Lyubaeva ÆP. P Tarakin ÆB. S Shenkman
A. B Vdovina ÆAleksei I Netreba ÆDaniil V Popov
O. L Vinogradova
SSC RF Institute for Biomedical Problems, 76A Khoroshevskoe
Chaussee, 123007, Moscow, Russia
H. E Montgomery
Institute for Human Health and Performance, University College
London, N19 5LW, London, UK
Eur J Appl Physiol (2006) 97: 103–108
DOI 10.1007/s00421-006-0154-4
muscle enzymes involved in fatty acid oxidation (FAO)
(Aoyama et al. 1998; Gulick et al. 1994; Schmitt et al.
2003). Chronic electrical stimulation of latissimus dorsi
muscle in dogs increased muscle PPARacontent and
medium-chain acyl-CoA dehydrogenase gene expression
(Cresci et al. 1996). These data suggest that PPARamay
be an important component of the adaptive response to
endurance training by transducing physiological signals
related to exercise training to the expression of nuclear
genes encoding in skeletal muscle mitochondrial FAO
enzymes.
Metabolization of carbohydrates and fatty acids
provides the primary means for energy production in
working skeletal muscle, whereby selection of these
substrates depends primarily on exercise intensity
(Brooks et al. 1994) and as we suppose, on gene vari-
ants involved in regulation of muscle metabolism.
Variation in the PPARagene influences plasma lipid
levels (Flavell et al. 2000; Vohl et al. 2000), cardiac
growth (Jamshidi et al. 2002), and risk of coronary
artery disease (Flavell et al. 2002).
Cardiac hypertrophy is associated with both de-
creased PPARaexpression (Barger et al. 2000) and
decreased FAO (Allard et al. 1994; Kagaya et al.
1990). Exercise-induced left ventricular (LV) growth in
healthy young men was strongly associated with the
intron 7 polymorphism of the PPARagene. Individ-
uals homozygous for the C allele had a threefold
greater and heterozygotes had a twofold greater in-
crease in LV mass than G allele homozygotes, leading
to the hypothesis that the hypertrophic effect of the
rare intron 7 C allele is due to influences on cardiac
substrate utilization (Jamshidi et al. 2002)—the C al-
lele being associated with reduced PPARaexpression
and FAO.
If PPARaexpression is a key regulator of the re-
sponse to physical training, then one might anticipate
genetic variation in the PPARagene to be associated
with human performance phenotypes. More specifically,
one might expect increased PPARaexpression and
FAO, and thus the intron 7 G allele, to be associated
with endurance performance. C allele carriers, on the
other hand, are speculated to be more predisposed to
intense anaerobic (power) performance by using mainly
glucose in muscle metabolism. We have tested this
hypothesis in the study of a mixed cohort of 786 Russian
athletes in 13 different sporting disciplines prospectively
stratified by performance (endurance-oriented athletes,
power-oriented athletes and athletes with mixed endur-
ance/power (acyclic) activity).
We also speculated that the C allele carriage (sug-
gested decreased PPARagene activity) would be
associated with a reduced proportion of type I (oxi-
dative/slow) fibers than GG homozygocity. To exam-
ine the association between PPARagene variant and
fiber type composition, muscle biopsies from m. vastus
lateralis were obtained and analyzed in 40 young
healthy men.
Materials and methods
The University of St Petersburg Ethics Committee ap-
proved the study and written informed consent was
obtained from each participant.
Subjects and controls
Seven hundred and eighty six male and female Russian
athletes of regional or national competitive standard
were recruited from the following sports: swimming
(n=58), track-and-field athletics (n=77), triathlon
(n=30), cross-country skiing (n=62), biathlon (n=28),
skating (n=72), road cycling (n=63), rowing (n=251),
boxing (n=22), ice hockey (n=15), wrestling (n=63),
court tennis (n=15) and weightlifting (n=30). The
athletes were prospectively stratified into groups
according to event duration and distance, covering a
spectrum from the more endurance-oriented to the more
power-oriented. The first group included middle (MDA)
and long distance athletes (LDA), such as 800–1,500 m
swimmers (race duration 8–15 min), triathletes, 3,000–
5,000 m skaters (race duration 4–7 min), biathletes,
cross-country skiers, road cyclists and rowers with pre-
dominantly aerobic energy production. The second
group comprised short distance athletes (SDA) (race
duration <70 s; 60–400 m runners, 500 m skaters, 50–
100 m swimmers) and weightlifters with predominantly
anaerobic energy production. The third group included
athletes whose sports utilized mixed anaerobic and aer-
obic energy production (court tennis players, wrestlers,
ice hockey players and boxers). Sixty-one athletes were
classified as ‘outstanding’, being at least national rep-
resentatives; the others were classified as ‘average’ ath-
letes, being regional competitors with no less than
4 years experience participating in their sport.
Controls consisted of 1,242 healthy unrelated pupils
(n=534, aged 11–12), students of different St Petersburg
Universities (n=535, aged 17–27) and St Petersburg
inhabitants (n=173, aged 20–42). The athletes and
control groups were all Caucasian Russians, with an
equivalent ratio from European and Siberian descent
(3:1 in both groups). Further characteristics are pre-
sented in Table 1.
Forty healthy men (aged 18–29; height
179.1±0.9 cm, weight 72.8±1.5 kg) gave their informed
consent to participate in muscle biopsy study which was
reviewed and approved by the Physiological Division of
the Russian National Bioethics Committee.
Genotyping
DNA was extracted from mouthwash samples as pre-
viously described (Bolla et al. 1995). Genotyping for the
intron 7 G/C (refsnp 4253778) variant was performed by
104
polymerase chain reaction (PCR) and restriction enzyme
digestion, as previously described (Flavell et al. 2002).
Muscle fiber typing
M. vastus lateralis was chosen for muscle biopsy because
of great individual variability of muscle fiber type
composition (i.e. 5–90% for type I fiber). Samples of m.
vastus lateralis of 40 young healthy men were obtained
with the Bergstrem needle biopsy procedure under the
local anesthesia with 1% lidocaine solution. Prior to
analysis, samples were frozen in liquid nitrogen and
stored at <80C. Serial sections (10 lm) were pre-
pared using a cryostat and microtome at 20C, with
sections then mounted on slides. The immunoperoxidase
technique was employed for immunohistochemical
identification of myosin isoforms. Antibodies against the
slow (MHCs) and fast (MHCf) myosin isoforms were
used (clones NCL–MHCf (a+c) and NCL–MHCs
(Novocastra Laboratories)). Sections incubated without
primary antibodies were to detect non-specific staining.
The antigen–antibody marking was intensified with the
Vectastain ABC kit (Vector Labs, CA) to visualize the
diaminebenzidine peroxidase reaction.
Fiber distribution was expressed as a ratio of the
number of fibers of each type in a section to the total
number of fibers. All fibers (no less than 40%) were
measured in each section. The cross-sectional area
(CSA) was determined for at least 100 fibers of each type
using image analysis system QUANTIMET-500 (Leica)
outfitted with color digital video camera JVC TK-1280E
(image resolution 720 ·512 pixels with 8 bit/pixel).
Sections to compare were prepared and stained all to-
gether with the Sigma (USA) reagents.
All analysis was done blind to genotype.
Statistical analysis
Allele frequencies were determined by gene counting.
Genotype distribution and allele frequencies between
groups of athletes and controls were then compared by
v
2
test. Frequency of the C alleles across the three
groups with different metabolic demands was compared
by v
2
test for linear trend by using the anaerobic com-
ponent as the categorical variable. The Spearman’s
correlation test was applied to the quantitative variables
(muscle fiber characteristics). Pvalues of <0.05 were
considered statistically significant.
Results
PPARaintron 7 genotype distributions amongst all
athletes and controls were in Hardy–Weinberg equilib-
rium. Genotype distribution amongst controls was
similar to that observed in other reported groups
(Jamshidi et al. 2002; Flavell et al. 2002,2005). No dif-
ference was found in C allele frequencies within groups
of controls (16.1% for pupils, 16.7% for students,
16.2% for St Petersburg inhabitants). The genotype
distribution and allele frequency amongst the whole
cohort was similar to that amongst sedentary controls
(Table 2).
We found an increasing linear trend of C allele
with increasing anaerobic component of physical per-
formance (P<0.029 for linear trend) (Fig. 1). Intron 7
C allele frequencies in endurance-oriented and power-
oriented events were 10.8% (P<0.0001, comparison
with controls) and 27.2% (P<0.0001, comparison
with controls), respectively. There was not significant
difference in C allele frequencies between the athletes
with mixed endurance/power activity and controls
(P=0.115). However, genotype distribution in ath-
letes with mixed endurance/power activity also
showed significant difference (P=0.012), compared to
controls.
In considering individual sporting disciplines, as
hypothesized, endurance-oriented athletes had signifi-
cantly higher percentage of GG genotype (MDA/LDA
swimmers (91.7%, P=0.021), cross-country skiers
(88.7%, P=0.0015), MDA/LDA skaters (87.9%,
P=0.026) and triathletes (86.7%, P=0.048)) compared
to controls (70.0%). Biathletes, road cyclists and rowers
did not show such significance.
There were significant differences in PPARagenotype
distribution only in ice hockey (P=0.032) and court
tennis players (P=0.047) within the group of mixed
endurance/power activity, compared to controls. In
power-oriented events group we found significantly ele-
vated frequencies of GC and CC genotypes, compared
to controls, so that C allele frequencies in SDA runners,
weightlifters, SDA skaters and SDA swimmers were
23.4% (P=0.024), 26.7% (P=0.034), 29.5% (P=0.002)
and 33.8% (P=0.0002), respectively.
Table 1 PPARaintron 7 genotype distribution of the athletes and
controls with sex (frequencies) and age
PPARaintron 7 genotype
GG, % GC, % CC, %
Athletes
All, n=786 71.5 25.1 3.4
Male, n=571 70.8 25.6 3.6
Female, n=215 73.0 24.2 2.8
Age, years 26±7 24±5 21±4
Sport experience, years 14±4 11±3 10±3
Controls
All, n=1242 70.0 27.3 2.7
Male, n=559 68.9 27.9 3.2
Female, n=683 71.0 26.8 2.2
Age, years 18±2 18±3 17±4
Muscle biopsy study
Male, n=40 62.5 27.5 10.0
Age, years 22±1 22±1 23±2
Values are means ± SE
GG wild-type homozygote; GC heterozygote; CC mutant homo-
zygote
105
It is worth mentioning that intron 7 C allele frequency
significantly correlated with elite athlete status. Linear
trends for increasing allele frequencies were also ob-
served with by ‘elite’ status for both power-oriented
(29.6% of C allele frequency in elite athletes (n=27),
P=0.0316) and endurance-oriented disciplines (92.2% of
G allele frequency in elite athletes (n=34), P<0.0001).
We also investigated the association of PPARain-
tron 7 polymorphism with physical performance sepa-
rately in male and female athletes (Fig. 2). Amongst
endurance-oriented athletes, C allele frequency in both
men (n=335, frequency 11.6%, P=0.004) and women
(n=156, frequency 9.0%, P=0.007), was significantly
different compared to controls. Similarly, in power-
oriented events group the strong association of C allele
was found both in men [n=131, frequency 26.7% vs.
controls (frequency 17.1%); P=0.0006] and women
[n=49, frequency 28.6% vs. controls (frequency
15.6%) P=0.003].
Interestingly, muscle fiber typing of 40 men showed
significant correlation between PPARaintron 7 poly-
morphism and muscle fiber specification. Mean per-
centages of type I fiber in GG homozygotes (n=25),
heterozygotes (n=11) and CC homozygotes (n=4) were
55.5±2.0, 44.7±2.6 and 38.5±2.3%, respectively
(r=0.55, P=0.0002). Furthermore, mean percentages of
type II fibers in GG homozygotes, heterozygotes and CC
homozygotes were 48.4±2.2, 58.1±3.3 and 61.0±2.1%,
respectively (r=0.48, P=0.0015). Mean CSA of type I
fiber in GG homozygotes was slightly bigger compared
to heterozygotes and CC homozygotes (5,479±274 vs
5,122±520 and 4,952±493 lm
2
, respectively), but this
correlation was non-significant.
Discussion
This is the first study to demonstrate that variation in
the PPARais associated with physical performance in
athletes and correlated with their elite status. Specifi-
cally, the intron 7 C allele seems associated with power-
orientated disciplines, and the G-allele with endurance
performance. Genotype distribution and C allele fre-
quencies in athletes with mixed power/endurance
activity were in intermediate position between endur-
ance- and power-oriented athletes, being similar to
controls.
Table 2 PPARaintron 7 genotype distribution and frequencies of PPARagene C allele in athletes stratified by power/endurance
orientation and sporting discipline. Comparison with controls was by v
2
test
Group Sport nGenotype Pvalue C allele, % Pvalue
GG, % GC, % CC, %
Endurance-oriented
events
Swimming
(800–1,500 m)
24 91.7 8.3 0 0.068 4.2 0.023*
Cross-country skiing 62 88.7 9.7 1.6 0.006* 6.4 0.003*
Triathlon 30 86.7 13.3 0 0.129 6.7 0.043*
Biathlon 28 85.7 14.3 0 0.178 7.1 0.063
Skating (3,000–5,000 m) 33 87.9 9.1 3.0 0.657 7.6 0.055
Road cycling 63 79.4 17.5 3.1 0.228 11.9 0.183
Rowing 251 74.9 23.1 2.0 0.281 13.5 0.113
All 491 80.3 17.9 1.8 0.0001* 10.8 0.0001*
Events with mixed
Power/endurance
(acyclic) activity
Boxing 22 72.7 22.7 4.6 0.817 15.9 0.933
Ice hockey 15 73.4 13.3 13.3 0.032* 20.0 0.595
Wrestling 63 63.5 30.2 6.3 0.199 21.4 0.138
Court tennis 15 66.7 20.0 13.3 0.047* 23.3 0.308
All 115 67.0 25.2 7.8 0.012* 20.4 0.115
Power-oriented
events
Running (60–400 m) 77 55.8 41.6 2.6 0.025* 23.4 0.024*
Weightlifting 30 53.3 40.0 6.7 0.107 26.7 0.034*
Skating (500 m) 39 43.6 53.8 2.6 0.001* 29.5 0.002*
Swimming (50–100 m) 34 44.1 44.1 11.8 0.0004* 33.8 0.0002*
All 180 50.6 44.4 5.0 0.0001* 27.2 0.0001*
Totals 786 71.5 25.1 3.4 0.397 16.0 0.725
Controls 1242 70.0 27.3 2.7 1.000 16.4 1.000
*P<0.05 statistically significant differences
0
5
10
15
20
25
30
Controls Aerobic
g
roup Mixed
g
roup Anaerobic
g
roup
C allele frequency, %
Fig. 1 PPARaintron 7 C allele frequency of 786 Russian athletes
and 1,242 controls is shown. C allele frequency in controls was
16.4%. By comparison, it was 10.8, 20.4 and 27.2% for
predominantly aerobic group (n=491), mixed aerobic and anaer-
obic group (n=115), and predominantly anaerobic group (n=180),
respectively (P=0.029 for linear trend)
106
Studies to date suggest that the C allele seems asso-
ciated with reduced PPARaexpression or function.
PPARaactivators (fibrates) reduce the incidence of
cardiovascular disease (CVD), whilst the intron 7 C
allele is associated with increased risk of CVD (Jamshidi
et al. 2002). Furthermore we have recently demonstrated
that the intron 7 C allele is associated with reduced re-
sponse to fenofibrate, a PPARaactivator (Foucher et al.
2004). We speculate that the intron 7 polymorphism is in
allelic association with an unidentified variant in a reg-
ulatory region of the PPARagene that affects PPARa
levels, which in turn affect transcriptional activation of
PPARatarget genes. Efforts to examine the effect of
intron 7 genotype on PPARamRNA levels and to
identify functional promoter variants are presently
underway.
Such findings suggest that the observed associations
are mediated through alterations in PPARaexpression.
The mechanisms through which such altered PPARa
activity influence athletic performance remain specula-
tive, and further in vitro and in vivo studies of gene
function are advocated. However, we might speculate
that the association of the C allele with power-oriented
performance relates to a propensity to skeletal muscle
hypertrophy, and a facilitation of glucose utilization
(rather than FAO) in response to anaerobic exercise. On
the other hand, the association of GG genotype with
endurance performance might relate to a propensity for
increased FAO.
In addition, PPARaexpression is raised in type I
(oxidative) rather than type II muscle fibers. However,
our data also suggest an allelic association not only
with function within a fiber type, but with fiber type
distribution itself: the G allele was associated with an
increased proportion of type I fibers when compared to
type II fibers. Such data are intriguing, and suggest a
potential influence of PPARaexpression on muscle fi-
ber differentiation. As successful endurance athletes
have relatively more slow-twitch than fast-twitch fibers
in the trained musculature (and sprinters an excess of
fast-twitch fibers), part of the allelic association with
performance phenotypes might have been mediated
though genotype-associated alterations in fiber type
proportion.
Our study does have limitations. The paucity of
functional data relating to the PPARaalleles needs to be
addressed with further in vitro studies. Further, the
association of PPARagenotype with alterations in
muscle function in response to training is advocated.
Our study also lacked biopsy data from elite athletes.
Finally, as in all such studies, extension to, and repli-
cation within other racial groups is proposed.
In summary, we have shown, for the first time, that
variation in the PPARagene is strongly associated with
physical performance in Russian athletes, and with
muscle fiber type in controls. Such findings have
important implications for our understanding of muscle
function in both health and disease.
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