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PPARα gene variation and physical performance in Russian athletes

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Peroxisome proliferator-activated receptor α (PPARα) regulates genes responsible for skeletal and heart muscle fatty acid oxidation. Previous studies have shown that the PPARα intron 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 increased 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). PPARα intron 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 performance (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 PPARα gene 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 (55.52.0 vs 38.52.3%) than CC homozygotes (n=4). In conclusion, PPARα intron 7 G/C polymorphism was associated with physical performance in Russian athletes, and this may be explained, in part, by the association between PPARα genotype and muscle fiber type composition.
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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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108
... SNVs are described in the coding region of the PPARGC1A gene, which are associated with muscle energy metabolism. SNV C23815662T (rs8192678) leads to the replacement of glycine with serine (Gly482Ser), which has a functional significance in the adaptation of skeletal muscles to physical stress [7,[28][29][30]. There is evidence that this SNV is associated with changes in blood lipids and insulin sensitivity. ...
... 306 SNVs are described in the coding region of the PPARGC1A gene, which are associ-307 ated with muscle energy metabolism. SNV C23815662T (rs8192678) leads to the replace-308 ment of glycine with serine (Gly482Ser), which has a functional significance in the adap-309 tation of skeletal muscles to physical stress [7,[28][29][30]. There is evidence that this SNV is The ability to engage in prolonged physical activity without significant moving speed reduction (e.g., long-distance running) is a process that uses oxidative metabolism [34]. ...
... 371 Lopez-Leon et al. [40] conducted a systematic review and meta-analysis to assess 372 whether there is an association between genotypes for this SNV and high sports perfor-373 mance in endurance. A total of 5 studies were analyzed [29,38,39,41,42] with the partici-374 pation of 760 endurance athletes and 1792 non-athletes (control group). The athletes rep-375 resented the following sports: rowing, marathon, biathlon, triathlon, cross-country skiing, 376 swimming, speed skating and cycling. ...
Article
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All biological processes associated with high sports performance, including energy metabolism, are influenced by genetics. DNA sequence variations in such genes, single nucleotide variants (SNVs), could confer genetic advantages that can be exploited to achieve optimal athletic performance. Ignorance of these features can create genetic “barriers” that prevent professional athletes from pursuing a career in sports. Predictive Genomic DNA Profiling reveals single nucleotide variations (SNV) that may be associated with better suitability for endurance, strength and speed sports. (1) Background: To conduct a research on candidate genes associated with regulation of skeletal muscle energy metabolism among athletes. (2) Methods: We have searched for articles in SCOPUS, Web of Science, Google Scholar, Clinical keys, PubMed, e-LIBRARY databases for the period of 2010–2020 using keywords and keywords combinations; (4) Conclusions: Identification of genetic markers associated with the regulation of energy metabolism in skeletal muscles can help sports physicians and coaches develop personalized strategies for selecting children, teenagers and young adults for endurance, strength and speed sports (such as jogging, middle or long distance runs). However, the multifactorial aspect of sport performances, including impact of genetics, epigenetics, environment (training and etc.), is important for personalized strategies for selecting of athletes. This approach could improve sports performance and reduce the risk of sports injuries to the musculoskeletal system.
... The usage of non-plasma fatty acids can be increased by continuing training, and by regulating gene expression, skeletal oxidative capacity may be increased. Ahmetov et al. (2006) reported that the rates of fatty acid oxidation in hepatic, myocardial, and skeletal muscle cells have risen among persons with PPARα GG and GC genotypes. In previous study, the authors also discovered a rise in the anaerobic metabolism in persons with PPARα CC genotype in which the endurance activities is likely to be beneficial for PPARα G allele. ...
... Furthermore, the GG genotype and the G variant in the non-athlete group were considerably greater compared to the athletes' frequency. The observed frequencies of G allele and GG genotype among Malay athletes are not consistent with the data from previous related studies on Polish (Maciejewska et al., 2011), Russian (Ahmetov et al., 2006), Lithuanian (Gineviciene et al., 2010), Italian (Proia et al., 2014), and Turkish population (Tural et al., 2014). Comparison of data from this study with prior studies indicated that the frequency of PPARα allele and genotype was not the same between populations. ...
... This result implies that C allele of the PPARα gene can be beneficial for muscle performance. The gene PPARα controls gene expression in many human enzymes participating in the oxidation of fatty acids (Ahmetov et al., 2006). Russell et al. (2003) noted that endurance training can improve the oxidative capability of skeletal muscles by expression of the PPARα gene, which enhances the utilisation of NFA. ...
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Background: This research examined the distribution and association of peroxisome proliferator-activated receptor alpha (PPARα) intron 7 G/C polymorphism with aerobic and anaerobic capacities, isokinetic muscular performance and bone speed of sound in Malay female athletes. Materials and Methods: A total of 64 young Malay female athletes (who competed at national level competitions) and non-athletes were recruited. DNA was taken from the subjects' blood samples. PCR-RFLP technique was used to determine the genotype of PPARα intron 7 G/C polymorphism. Participants' body composition, lung function parameters, estimated VO 2max and anaerobic capacity were measured. Participants' leg and arm isokinetic muscular the maximum torque (strength), maximum torque per body weight and average power have been evaluated. Tibial and radial bone speed of sound was assessed using qualitative ultrasound (indicator of bone mineral density). Results: GG genotype was the most frequent PPARα genotype observed in both Malay female athlete and non-athlete groups. The GG genotype in the non-athlete group was somewhat greater than in the athletic group. Athletes with GC genotype exhibited substantially greater (p < 0.05) isokinetic muscular strength in the arm compared to athletes with GG genotype. In addition, GC genotype carriers demonstrate significantly elevated bone speeds of arm sound than GG genotype carriers. Athletes with GG genotype showed significantly higher (p < 0.01) forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) compared to non-athletes with GG genotype. GG-genotype athletes were substantially have higher estimated VO 2max , Wingate mean power, peak power, and anaerobic capacities in comparison to non-athletes with GG genotype. Conclusions: In Malay female athletes, GC genotype appears to be associated to increased muscular strength and improved bone health.
... Further studies recruiting athletes that represented different sports disciplines have revealed that it was more likely to find C allele carriers in a group of power-oriented athletes who were involved in short and very intense anaerobic effort (Ahmetov et al., 2006), while GG homozygotes were more prevalent among endurance-type athletes performing predominantly prolonged aerobic exertion (Eynon et al., 2010;Maciejewska et al., 2011). Gineviciene et al. (2010) confirmed the results of previous studies in Lithuanian male athletes showing that those with allele PPARA rs4253778 C had significantly higher muscle mass and better results in explosive strength of lower extremities © Editorial Committee of Journal of Human Kinetics than GG homozygotes (Ginevičienė et al., 2010). ...
... Those results were in part explained by the analysis of muscle fiber composition of young men. It was shown that GG homozygotes had a higher percentage of slow-twitch fibers compared to CC homozygotes and the C allele was associated with the propensity to skeletal muscle hypertrophy (Ahmetov et al., 2006). ...
... It has been shown that there was a tendency for power oriented athletes (ie. 60-400 m runners, 500 m skaters, 50-100 m swimmers and weightlifters) to possess the C allele or the CC genotype rather than the GG © Editorial Committee of Journal of Human Kinetics genotype (Ahmetov et al., 2006). The C allele carriers had also significant hypertrophy of skeletal muscle (due to a higher percentage of fast twitch fibers), what may facilitate glucose utilization in response to anaerobic exercise resulting in higher muscle mass. ...
Article
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Athletic ability is influenced by several exogenous and endogenous factors including genetic component. Hundreds of gene variants have been proposed as potential genetic markers associated with fitness-related phenotypes as well as elite-level athletic performance. Among others, variants within the PPARA gene that code for the peroxisome proliferator activated receptor α are of potential interest. The main goal of the present study was to determine PPARA (G/C, rs4253778) genotype distribution among a group of Polish, Lithuanian and Italian international level male gymnasts and to compare our findings with those of previous research on the frequency of the PPARA intron 7 C allele/CC genotype in power/strength-oriented athletes. A total of 464 male subjects (147 gymnasts and 317 controls) from Poland (n = 203), Italy (n = 146) and Lithuania (n = 107) participated in the study. No statistically significant differences were found in any of the analyzed cohorts. However, a significantly higher frequency of the CC genotype of the PPARA rs4253778 polymorphism was observed when all gymnasts were pooled and compared with pooled control using a recessive model of inheritance (OR = 3.33, 95% CI = 1.18-10, p = 0.022). It is important to know that we investigated a relatively small sample of male European gymnasts and our results are limited only to male participants. Thus, it is necessary to validate our results in larger cohorts of athletes of different ethnicities and also in female gymnasts to find out whether there is a gender effect.
... PPARA genas yra vienas pirmųjų nustatytų genų kandidatų, siejamų su fiziniu pajėgumu ir elito sportininko statusu (Ahmetov et al., 2006). Literatūros duomenimis, PPARα yra svarbus komponentas organizmo adaptacijoje prie fizinių krūvių, dalyvauja angliavandenių ir lipidų apykaitoje, reguliuoja kūno svorį, taip pat reguliuoja kelių pagrindinių raumenų fermentų, dalyvaujančių RRO, genų raišką (Eynon et al., 2010). ...
... PPARA gene nustatytos kelios polimorfinės vietos, tačiau tiriant aukšto meistriškumo sportininkų savybes reikšmingas yra PPARA G/C polimorfizmas (rs4253778) (1 lentelė) (Cieszczyk et al., 2011). Nors šis polimorfizmas yra PPARA geno introninėje dalyje, jis yra funkciškai reikšmingas, nes sąveikauja su promotoriaus ir slopintuvo / stiprintuvo elementais funkcinėje geno dalyje (Ahmetov et al., 2006). Mokslininkų nustatyta, kad PPARA geno 7 introno G alelis yra susijęs su padidėjusia PPARA geno raiška (ir PPARα baltymo lygių) fizinio krūvio metu ir gali būti reikšmingai susijęs su didesniu ištvermės potencialu, sustiprinant RRO ir tokiu būdu išsaugodamas energiją, reikalingą ilgesniam darbui atlikti (Semenova et al., 2019). ...
... Taigi literatūros analizė parodė, kad PPARA C alelis dažnesnis jėgos ir greitumo sportininkų grupėse, be to, nustatyta jo asociacija su didesne greitai susitraukiančių raumenų skaidulų (IIa ir IIb tipo) proporcija. Remiantis mokslininkų atliktais darbais, nustatyta, kad PPARA G alelis siejamas su ištvermės savybėmis, o C alelis su greitumo ir jėgos (Ahmetov, 2006). Tai patvirtina ir tyrimas, atliktas Lietuvoje, analizuojant aukšto meistriškumo sportininkus. ...
... Sports scientists have long been investigating the relationship between the PPAR-A gene polymorphisms and aerobic performance in sports that require endurance. Recently, many researchers have reported that the PPAR GG genotype offers an advantage for athletes engaged in endurance sports (Lucia et al., 2005;Ahmetov II et al., 2006;Krämer et al., 2006). ...
... It has been reported that the PPARA rs4253778 GG genotype and G allele frequency was statistically higher in five researches, including a group of 77 elite male Czech ice hockey players (Petr et al., 2015), 760 endurance athletes and 1792 controls (Lopez-Leon et al., 2016), elite Polish rowers and combat athletes (Maciejewska et al., 2011) and Russian athletes engaged in endurance sports (Ahmetov II et al., 2006) as compared with sedentary control group and/or sprinters. ...
... It has been shown that PPAR-a GG genotype is associated with high oxygen pulse (Ahmetov II et al., 2013). For this reason, this genotype is one of the important genetic markers of intense aerobic exercise such as endurance phenotype (Ahmetov II et al., 2006). ...
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The purpose of this study was to examine the effects of PPAR-a (rs4253778) on serum lipids in elite cross-country skiers. This study included 34 cross-country skiers (23 males and 11 females who participated in the Turkish skiing national team camp). Genotyping for the PPAR-a gene rs4253778 G/C polymorphism was performed by PCR on Tercyk multicanal amplificator and restriction enzyme digestion. Statistical analysis was done by using the SPSS 22.0 package program. Genotypic frequency of the PPAR-a polymorphism was detected in cross-country skiers. PPAR-a GG, GC and CC genotypes were detected as 67.64%, 23.52% and 8.82%, respectively in 34 cross-country skiers while PPAR-a GG, GC and CC genotypes were detected as 47.05%, 16.64%, and 2.94%, respectively in elite males. PPAR-a GG, GC and CC genotypes were detected as 20.58 %, 5.88%, and 5.88%, respectively in females. PPAR-a G and C allele were detected as 49 and 19, respectively in 34 elite endurance athletes. In the present study, the GG genotypes were detected at higher frequencies in elite athletes (67.64% respectively) than GC and CC (23.52% and 8.82%, respectively). The difference between the PPAR-a G/C gene polymorphism of Turkish elite cross-country skiers and serum total cholesterol, HDL- cholesterol, LDL- cholesterol and TG levels was not statistically significant. Although there was not any statistically significant difference between the PPAR-a G/C gene polymorphism and lipid profiles of Turkish elite cross-country skiers, it is foreseen that PPAR-α genes have an important effect on endurance performance in sports requiring endurance such as cross-country skiing.
... Interestingly, a naturally occurring Arg213Gly polymorphism in this binding region [15] increases the extracellular SOD concentration in the plasma of homozygous individuals 10-to 30-fold [16]. Furthermore, the Peroxisome Proliferator-Activated α-Receptor (PPARα) regulates both systemic redox activity [17] and the oxidative capacity of skeletal muscles [18,19]. In addition, it is involved in mitochondrial activity, which directly influences endurance exercises [20]. ...
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Background We examined the influence of superoxide dismutase 3 (SOD3) Arg213Gly and Peroxisome Proliferator-Activated α-Receptor (PPARα) 7G/C polymorphisms to a single dose of purple grape juice supplementation on time-to-exhaustion running test, redox balance and muscle damage in recreational runners. Methods Forty-seven male recreational runners performed a running test until exhaustion after supplementation with grape juice or a control drink. Serum total antioxidant capacity (TAC), malondialdehyde (MDA), plasma nitrite (NO), creatine kinase (CK) and lactate dehydrogenase (LDH) were measured pre and post exercise. Also, polymorphisms were analyzed in DNA extracted from the oral mucosa. Results Grape juice improved the time-to-exhaustion. When analyzed by genotype, the recreational runners with GG+CG genotypes of the SOD3 gene had greater time-to-exhaustion than the CC genotype, but was no different for the PAPRα gene. A slight difference was noted in TAC, since the CC genotype of the SOD3 gene showed higher TAC values in the post-exercise compared to the baseline and with pre-exercise, but these values did not increase compared to the CG+GG group, respectively. The SOD3 and PPARα genes were similar at all times for the other biochemical variables. Conclusion The ergogenic effect of grape juice was genotype-dependent for SOD3 Arg213Gly. However, biochemical redox balance markers did not explain this difference.
... There are findings indicating that PPARA gene G/C polymorphism is associated with swimming performance. The G allele was over-represented in LDS compared to controls (95.8 vs 83.6%; P = 0.023), while the C allele was overrepresented in SDS compared to controls (33.8 vs 16.4%; P = 0.0002) [104]. A meta-analysis on 760 endurance athletes, including swimmers, and 1792 controls, found higher frequency of the GG genotype and G allele among athletes compared to controls [105]. ...
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A successful swimming performance is a multi-factorial accomplishment, resulting from a complex interaction of physical, biomechanical, physiological and psychological factors, all of which are strongly affected by the special medium of water as well as by genetic factors. The nature of competitive swimming is unique, as most of the competitive events last less than four minutes. Yet training regimens have an endurance nature (many hours and many kilometres of swimming every day), which makes it impossible to classify swimming by definitions of aerobic-type or anaerobic-type events, as in track and field sports. Therefore, genetic variants associated with swimming performance are not necessarily related to metabolic pathways, but rather to blood lactate transport (MCT1), muscle functioning (IGF1 axis), muscle damage (IL6) and others. The current paper reviews the main findings on the leading 12 genetic polymorphisms (located in the ACE, ACTN3, AMPD1, BDKRB2, IGF1, IL6, MCT1, MSTN, NOS3, PPARA, PPARGC1A, and VEGFR2 genes) related to swimming performance, while taking into consideration the unique environment of this sport.
... PPARGC1A (peroxisome proliferator-activated receptor gamma co-activator-1-alpha) is an inducible transcription coactivator, which can participate in many life activities by promoting mitochondrial energy metabolism, such as adaptive thermogenesis, skeletal muscle fiber type conversion, glucose/ fatty acid metabolism, and cardiac development (Fontecha-Barriuso et al., 2020). Some studies showed that PPARGC1A gene controls the expression of several genes encoding key enzymes involved in fatty acid oxidation and mainly regulates the induction of muscle adaptation training (Ahmetov et al., 2006). Endurance training can increase PPARGC1A mRNA expression (Franks et al., 2003). ...
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Objective: The manuscript aims to explore the relationship between power performance and SNPs of Chinese elite athletes and to create polygenic models. Methods: One hundred three Chinese elite athletes were divided into the power group ( n = 60) and endurance group ( n = 43) by their sports event. Best standing long jump (SLJ) and standing vertical jump (SVJ) were collected. Twenty SNPs were genotyped by SNaPshot. Genotype distribution and allele frequency were compared between groups. Additional genotype data of 125 Chinese elite athletes were used to verify the screened SNPs. Predictive and identifying models were established by multivariate logistic regression analysis. Results: ACTN3 (rs1815739), ADRB3 (rs4994), CNTFR (rs2070802), and PPARGC1A (rs8192678) were significantly different in genotype distribution or allele frequency between groups ( p < 0.05). The predictive model consisted of ACTN3 (rs1815739), ADRB3 (rs4994), and PPARGC1A (rs8192678), the area under curve (AUC) of which was 0.736. The identifying model consisted of body mass index (BMI), standing vertical jump (SVJ), ACTN3, ADRB3, and PPARGC1A, the area under curve (AUC) of which was 0.854. Based on the two models, nomograms were created to visualize the results. Conclusion: Two models can be used for talent identification in Chinese athletes, among which the predictive model can be used in adolescent athletes to predict development potential of power performance and the identifying one can be used in elite athletes to evaluate power athletic status. These can be applied quickly and visually by using nomograms. When the score is more than the 130 or 148 cutoff, it suggests that the athlete has a good development potential or a high level for power performance.
... However, the muscle fiber type is a complex trait, which is influenced by several different genes, in which each DNA locus is usually responsible for a small percentage of phenotypic variability. Multiple genes like angiotensin I converting enzyme (ACE) (Zhang et al., 2003), alpha-actinin-3 (ACTN3) (Vincent et al., 2007) and peroxisome proliferator-activated receptor alpha (PPAR-α) (Ahmetov et al., 2006) have been associated with the muscle fiber type composition. Notwithstanding, the majority of associations have not been reproduced in independent samples (Semenova et al., 2019). ...
Thesis
The human skeletal muscle consists of two major cell types, slow-twitch fibers (also called type I fibers) and fast-twitch fibers (or type II fibers). These fibers have distinct characteristics, as fast-twitch fibers are able to generate a large amount of power at high shortening velocities, while slow-twitch fibers have a better energy efficiency, a higher resistance to fatigue and a more robust structural integrity. On average, most humans will dispose of a 50% slow-twitch and a 50% fast-twitch distribution. However a big heterogeneity exists, what results in people with predominantly slow or fast muscle fibers. The typology of a person is mostly genetically determined and is present across most muscles of the body. Taken together, the fact that muscle fibers have distinct characteristics and that muscle typologies range over the whole continuum from predominantly slow to fast in human, will have important implications for sports performance. Nevertheless, these typologies are currently not used in the daily coaching practice. This is probably due to the invasiveness of the current ‘gold’ standard to measure the muscle typology: a muscle biopsy, which is a labor intensive method and harbors a low generalizability. In 2011, our group introduced a non-invasive way to estimate the muscle fiber type composition through the measurement of carnosine – a metabolite which is abundantly available in fast-twitch fibers – using proton magnetic resonance spectroscopy (1H-MRS). The non-invasiveness of this technique enables the use in both the sports practice and science, and renews the interest of the muscle typology in sports. In the first study, the 1H-MRS method to determine the muscle typology was further optimized with the ultimate goal to make it applicable on various scanner systems of multiple vendors. 1H-MRS was found to be a reliable method to quantify carnosine in the muscle. Furthermore, best practices were proposed to prevent often encountered methodological problems and step by step guidelines were developed to allow broader utilization of this technique. Secondly, we investigated if pre-puberty carnosine measurements could give insights in the post-puberty carnosine concentrations, which would allow application of this technique in early specialization sports (study 2). Carnosine was shown to be a trackable metabolite through the disruptive puberty period (R2=0.249-0.670), which confirms the potential of the current technique to scan both future talents and elite athletes. Next to the methodological optimization, the relevance of the muscle typology for talent identification was examined. Before the start of the thesis, the construct validity of our method was already confirmed in athletics, in which clear differences were determined in the muscle typology of either sprint or endurance disciplines. Despite the fact that a comparable distribution of the muscle typologies could be expected in other cyclic sports such as cycling and swimming, this was not yet investigated in elite athletes. Therefore, study 3 established the muscle typologies of 80 world-class cyclists. Clear differences were found in the muscle typology between cycling events. Keirin, bicycle motocross racing (BMX), sprint and 500 m to 1 km time trial cyclists can be considered as fast typology athletes. Time trial, points race, scratch, and omnium consist of intermediate typology athletes, while most individual pursuit, single-stage, cyclo-cross, mountain bike, and multistage cyclists have a slow typology. Nevertheless, this distribution was not present in 73 elite swimmers (study 4), as no clear differences in the muscle typology were detected between short and long distance swimming events in the different strokes. However, there was some evidence to suggest that truly world-class sprint swimmers had a faster muscle fiber type composition when compared to elite swimmers competing at the international level. Moreover, breaststroke swimmers were identified to have a faster muscle typology in comparison to the either freestyle, backstroke or butterfly swimmers. Elite soccer players (n=118) were found to have an on average intermediate typology, which matches with the intermittent nature of this sport (study 6). In contrary to our hypothesis, no differences in the muscle typology were detected between different positions (keeper, defender, midfielder and striker). A big heterogeneity was established over all positions, indicating that the muscle typology is not of major importance for talent identification in soccer. To determine the influence of the muscle typology on individualized training and recovery cycles, we investigated if fatigue and recovery were different when both slow and fast typology subjects were exposed to the same high-intensity training (study 5). Fatigue during three Wingate tests, determined by the power drop, was 20% higher in fast typology athletes. Even though the same work was done during these Wingate tests, also the recovery from these Wingate tests was found to be 15 times slower in fast typology athletes (20 min in slow typology vs. longer than 5 h in fast typology). If a training plan would be composed with a minimum of recovery in between the training sessions, recovery might be insufficient for fast typology athletes, possibly rendering them with a higher risk for muscle strains. In study 6, we studied if the muscle typology is a risk factor for muscle strains in elite soccer players. We discovered that fast typology soccer players had a 5.3 times higher chance to get a hamstring injury, when compared to slow typology soccer players during a prospective longitudinal follow-up study over three seasons. Next to a higher accumulation of fatigue, a higher vulnerability in fast typology players could be expected due to the lower structural integrity in fast fibers. Bringing together, the muscle typology is an important characteristic, which could be non-invasively monitored using 1H-MRS. This technique could help athletes to make a scientific based decision on their ideal discipline during talent orientation. Moreover, it could help coaches tailoring training to enlarge the athletes’ muscle potential and to prevent fatigue accumulation. This endeavor might partly prevent fast typology athletes to be at a higher risk for strain injuries. Consequently, we believe that measuring the muscle fiber typology of athletes should be considered as a valuable procedure to help athletes to fully develop their potential based on the smart use of muscle profiling.
Article
Sports genomics is the scientific discipline that focuses on the organization and function of the genome in elite athletes, and aims to develop molecular methods for talent identification, personalized exercise training, nutritional need and prevention of exercise-related diseases. It postulates that both genetic and environmental factors play a key role in athletic performance and related phenotypes. This update on the panel of genetic markers (DNA polymorphisms) associated with athlete status and soft-tissue injuries covers advances in research reported in recent years, including one whole genome sequencing (WGS) and four genome-wide association (GWAS) studies, as well as findings from collaborative projects and meta-analyses. At end of 2020, the total number of DNA polymorphisms associated with athlete status was 220, of which 97 markers have been found significant in at least two studies (35 endurance-related, 24 power-related, and 38 strength-related). Furthermore, 29 genetic markers have been linked to soft-tissue injuries in at least two studies. The most promising genetic markers include HFE rs1799945, MYBPC3 rs1052373, NFIA-AS2 rs1572312, PPARA rs4253778, and PPARGC1A rs8192678 for endurance; ACTN3 rs1815739, AMPD1 rs17602729, CPNE5 rs3213537, CKM rs8111989, and NOS3 rs2070744 for power; LRPPRC rs10186876, MMS22L rs9320823, PHACTR1 rs6905419, and PPARG rs1801282 for strength; and COL1A1 rs1800012, COL5A1 rs12722, COL12A1 rs970547, MMP1 rs1799750, MMP3 rs679620, and TIMP2 rs4789932 for soft-tissue injuries. It should be appreciated, however, that hundreds and even thousands of DNA polymorphisms are needed for the prediction of athletic performance and injury risk.
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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that can be activated by various xenobiotics and natural fatty acids. These transcription factors primarily regulate genes involved in lipid metabolism and also play a role in adipocyte differentiation. We present the expression patterns of the PPAR subtypes in the adult rat, determined by in situ hybridization using specific probes for PPAR-alpha, -beta and -gamma, and by immunohistochemistry using a polyclonal antibody that recognizes the three rat PPAR subtypes. In numerous cell types from either ectodermal, mesodermal, or endodermal origin, PPARs are coexpressed, with relative levels varying between them from one cell type to the other. PPAR-alpha is highly expressed in hepatocytes, cardiomyocytes, enterocytes, and the proximal tubule cells of kidney. PPAR-beta is expressed ubiquitously and often at higher levels than PPAR-alpha and -gamma. PPAR-gamma is expressed predominantly in adipose tissue and the immune system. Our results suggest new potential directions to investigate the functions of the different PPAR subtypes.
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Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes a pivotal reaction in mitochondrial fatty acid (FA) beta-oxidation. To examine the potential role of FAs and their metabolites in the regulation of MCAD gene expression, we measured MCAD mRNA levels in animals fed inhibitors of mitochondrial long-chain FA import. Administration of carnitine palmitoyltransferase I inhibitors to mice or rats resulted in tissue-limited increases in steady-state MCAD mRNA levels. HepG2 cell cotransfection experiments with MCAD promoter reporter plasmids demonstrated that this was a transcriptional effect mediated by the peroxisome proliferator-activated receptor (PPAR). The activity mapped to a nuclear receptor response element that functioned in a heterologous promoter context and specifically bound immunoreactive PPAR in rat hepatic nuclear extracts, confirming an in vivo interaction. PPAR-mediated transactions of this promoter and element were also induced by exogenously added FA and fibric acid derivatives. Induction of PPAR transactivation by perturbation of this discrete metabolic step is unusual and indicates that intracellular FA metabolites that accumulate during such inhibition can regulate MCAD expression and are likely candidates for PPAR ligand(s). These results dictate an expanded role for the PPAR in the regulation of FA metabolism.
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Background — Left ventricular hypertrophy (LVH) occurs as an adaptive response to a physiological (such as exercise) or pathological (valvular disease, hypertension, or obesity) increase in cardiac work. The molecular mechanisms regulating the LVH response are poorly understood. However, inherited defects in fatty acid oxidation are known to cause severe early-onset cardiac hypertrophy. Peroxisome proliferator–activated receptor α (PPARα) regulates genes responsible for myocardial fatty acid oxidation and is downregulated during cardiac hypertrophy, concomitant with the switch from fatty acid to glucose utilization. Methods and Results — The role of PPARα in left ventricular growth was investigated in 144 young male British Army recruits undergoing a 10-week physical training program and in 1148 men and women participating in the echocardiographic substudy of the Third Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg study. A G/C polymorphism in intron 7 of the PPARα gene significantly influenced left ventricular (LV) growth in response to exercise ( P =0.009). LV mass increased by 6.7±1.5 g in G allele homozygotes but was significantly greater in heterozygotes for the C allele (11.8±1.9 g) and in CC homozygotes (19.4±4.2 g). Likewise, C allele homozygotes had significantly higher LV mass, which was greater still in hypertensive subjects, and a higher prevalence of LVH in the Third MONICA Augsburg study. Conclusions — We demonstrate that variation in the PPARα gene influences human left ventricular growth in response to exercise and hypertension, indicating that maladaptive cardiac substrate utilization can play a causative role in the pathogenesis of LVH.
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To investigate the effects of long-term pressure overload on regional myocardial substrate use, we performed quantitative autoradiography using 2-deoxy-D-[U-14C]glucose (14C-DG) and beta-methyl[1-14C]heptadecanoic acid (14C-BMHDA) in conscious rats with a 10-week ascending aortic constriction. Heart weight/body weight ratio increased by 27% in aortic-constricted rats as compared with sham-operated rats (p less than 0.01). Myocardial 14C-DG uptake increased (258 +/- 63 vs. 144 +/- 41 nCi/g, p less than 0.01, n = 6 for each group); however, 14C-BMHDA extraction decreased (251 +/- 69 vs. 342 +/- 75 nCi/g, p less than 0.05, n = 7 for each group) in aortic-constricted rats as compared with sham-operated rats. In sham-operated rats, both 14C-DG and 14C-BMHDA uptakes were higher in the left ventricular anterior and lateral walls as compared with the posterior wall or the interventricular septum. In aortic-constricted rats, 14C-DG uptake also increased in the interventricular septum, as well as in the left ventricular anterior and lateral walls, as compared with the posterior wall. There was, however, no regional difference in 14C-BMHDA extraction among these four regions. Myocardial blood flow distribution determined by 4-[N-methyl-14C]iodoantipyrine or myocyte width showed no regional variations among the four regions, either in aortic-constricted or sham-operated rats. Regional interstitial fibrosis was small in either group. The present study suggests that myocardial substrate uptake is altered nonhomogeneously, and that the nonhomogeneity is not because of regional variations in blood flow distribution, myocyte hypertrophy, or interstitial fibrosis. The results of angiotensin II-induced acute pressure overloading in other sham-operated rats, in which a remarkable increase in myocardial 14C-BMHDA extraction (n = 3, p less than 0.01) and no difference in 14C-DG uptake (n = 3) as compared with normotensive sham-operated rats were elicited, suggest that the findings in aortic-constricted rats are not direct responses to increased left ventricular pressure itself but rather should be explained by still unknown factors related to prolonged pressure overload.
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Molecular epidemiological research has identified the association of a common apolipoprotein E (apo E) isoform (E4 as opposed to E3), with risk both of coronary artery disease and of Alzheimer dementia. In addition, the role of apo E genotype (usually E2/E2) in Type III hyperlipidemia is well known. However, both for diagnostic and research purposes, apo E genotyping is cumbersome. The preferred approach is electrophoretic sizing of restriction digestion fragments, enabling simultaneous analysis of the two codons (112 and 158) that represent the six common genotypes (E2/E2; E2/E3; E2/E4; E3/E3; E3/E4; E4/E4). However, the consequent demands of high-yield PCR, high-resolution, high-throughput electrophoresis, and sufficient detection sensitivity have left shortfalls in published protocols. In conjunction with a high-throughput electrophoresis system we described recently, microplate array diagonal gel electrophoresis (MADGE), we have constructed extensively optimized, simplified protocols for DNA isolation from mouthwash samples for PCR setup and high-yield PCR, for restriction digestion, and for subsequent MADGE gel image analysis. The integral system enables one worker to readily undertake apo E genotyping of as many as hundreds of DNA samples per day, without special equipment.
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The contribution of glycolysis and oxidative metabolism to ATP production was determined in isolated working hypertrophied hearts perfused with Krebs-Henseleit buffer containing 3% albumin, 0.4 mM palmitate, 0.5 mM lactate, and 11 mM glucose. Glycolysis and glucose oxidation were directly measured by perfusing hearts with [5-3H/U-14C]glucose and by measuring 3H2O and 14CO2 production, respectively. Palmitate and lactate oxidation were determined by simultaneous measurement of 3H2O and 14CO2 in hearts perfused with [9,10-3H]palmitate and [U-14C]lactate. At low workloads (60 mmHg aortic after-load), rates of palmitate oxidation were 47% lower in hypertrophied hearts than in control hearts, but palmitate oxidation remained the primary energy source in both groups, accounting for 55 and 69% of total ATP production, respectively. The contribution of glycolysis to ATP production was significantly higher in hypertrophied hearts (19%) than in control hearts (7%), whereas that of glucose and lactate oxidation did not differ between groups. During conditions of high work (120 mmHg aortic afterload), the extra ATP production required for mechanical function was obtained primarily from an increase in the oxidation of glucose and lactate in both groups. The contribution of palmitate oxidation to overall ATP production decreased in hypertrophied and control hearts (to 40 and 55% of overall ATP production, respectively) and was no longer significantly depressed in hypertrophied hearts. Glycolysis, on the other hand, was accelerated in control hearts to rates seen in the hypertrophied hearts. Thus a reduced contribution of fatty acid oxidation to energy production in hypertrophied rat hearts is accompanied by a compensatory increase in glycolysis during low work conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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To determine whether expression of a nuclear gene encoding a mitochondrial fatty acid oxidation enzyme is regulated in parallel with skeletal muscle fibre-type-specific energy substrate preference, expression of the gene encoding medium-chain acyl-CoA dehydrogenase (MCAD) was delineated in canine latissimus dorsi muscle subjected to chronic motor nerve stimulation. In predominantly fast-twitch canine latissimus dorsi muscle, MCAD mRNA levels were regulated by chronic stimulation in a biphasic pattern. During the 1st wk of stimulation, steady-state MCAD mRNA levels decreased to 50% of unstimulated levels. MCAD mRNA levels began to increase during the 3rd wk of stimulation to reach a level 3.0-fold higher than levels in unstimulated contralateral control muscle by day 70. Immunodetectable MCAD mRNA levels throughout the stimulation period. The temporal pattern and magnitude of MCAD mRNA accumulation in response to muscle stimulation was distinct from that of mRNAs encoding other enzymes known to be regulated by this stimulus, including glyceraldehyde phosphate dehydrogenase, citrate synthase, and sarcoplasmic reticulum Ca-ATPase, but paralleled the protein levels of the peroxisome proliferator-activated receptor (PPAR), an orphan member of the nuclear hormone receptor superfamily known to regulate genes encoding fatty acid oxidation enzymes in liver. The skeletal muscle expression pattern of PPAR was also similar to that of MCAD in unstimulated rat skeletal muscles with distinct fiber-type compositions. These results demonstrate that a nuclear gene encoding a mitochondrial beta-oxidation enzyme is dynamically regulated in a pattern that parallels skeletal muscle fiber-type-specific energy substrate utilization and implicate an orphan nuclear receptor transcription factor as a candidate transducer of this response.