Review article
Volume 3, No. 1, 2011, 23-29
UDC 575.113:612.74
Vladimir Gali„
Department of Physiology
Medical faculty Novi Sad
Skeletal muscle is extremely adaptable to various stresses which can be placed upon it. In
spite of importance of skeletal muscles, little is known about genetic factors which demonstrate
high influence to muscle size, function, strength and adaptation to various environmental factors.
Because endurance performance is a multifactorial trait, the list of candidate genes which could
account for human variation in related phenotypes is extensive. One of the first characterized and
most frequently studied genetic variant is a polymorphism in the angiotensin converting enzyme
I gene. The ACTN3 gene is the first structural skeletal muscle gene with a relation between its
genotype and elite sprinterí performance. Nevertheless, current genetic testing cannot provide an
extra advantage over existing testing methods in determining sports selection in young athletes.
The main challenge still remains to identify other, complex polygenetic variants and their
interactions with environmental factors which could provide benefit in the sports selection and
existing talent identification.
Keywords: exercise genomics, genetic polymorphism, muscle tissue
Muscle tissue constitutes approximately 30% of body mass, it is metabolically very
active with high turnover of energy and is capable of efficient response to different
environmental stimuli. Skeletal muscle is extremely adaptable to various stresses which can be
placed upon it. These adaptations can be either positive, such as tissue growth, extreme athletic
performance or reparation of an injury, or negative, such as decline in mass and function over the
years of disuse or disease. Muscle strength is one of the most important determinants of oneís
functional ability and can influence some other tissues, like bone tissue by maintaining its
Corresponding author. Department of Physiology, Medical faculty Novi Sad. Hajduk Veljkova 3, 21000 Novi Sad.
E-mail: galic.ns@gmail.com
© 2010 Faculty of Sport and Physical Education, University of Novi Sad, Serbia
V. Gali
density throughout a lifetime. In spite of such importance of skeletal muscles, little is known
about genetic factors which demonstrate high influence to muscle size, function, strength and
adaptation to various environmental factors. Besides that, there is a diversity of information in
literature related to heritability of muscle characteristics. According to research of Bouchard and
his coworkers, whose main goal was to review all known genetic loci related to physical
performance or health-related fitness, there are more than 200 autosomal chromosome genes,
seven genes on the X chromosome and 18 mitochondrial genes that have been shown to
influence fitness and performance phenotypes (Bouchard et al., 2008). The physical performance
human phenotypes include cardio-respiratory endurance, muscle strength and exercise
intolerance. On the other hand, the health-related fitness phenotypes could be grouped in several
categories: exercise heart rate, blood pressure, body composition, insulin and glucose
metabolism, blood lipid and haemostatic factors (Bouchard et al., 2008). Despite all up-to-date
published information, majority of studies cannot establish a definitive relationship between
genotype and phenotype. The main reason for this uncertainty is small effect of a particular gene
on fitness or health-related traits and as a consequence, in order to achieve a significant ratio, it is
necessary to have above 1000 cases with as many controls. On the other hand, if the subjects are
examined in well-controlled laboratory conditions the sample size could be lower. However,
obtained results should be interpreted cautiously until other similar studies confirm initial
findings and assumptions.
Heritability of performance and health-related characteristics
One of the first strong evidence for a genetic influence on physical performance was
obtained from studies which compared related individuals with unrelated subjects in order to
discover heritability for several aerobic and cardiac-related characteristics (MacArthur, 2005).
Generally, genetic factors are thought to determine 20-80% of changes in a range of traits related
to elite athletic performance (MacArthur, 2007). Researchers estimate that performance related
traits have heritability values of approximately 50% for maximal oxygen uptake (VO2 max), 42-
46% for stroke volume and cardiac output during sub maximal exercise, 40-50% for muscle fiber
type proportions, and 67% for explosive muscle power (MacArthur, 2004). Considerable genetic
effects have been discovered for measures of skeletal muscle strength and performance, such as
muscle adaptation to endurance exercise
(Hamel et al.,
1986) or anaerobic capacity and
explosive power (Calvo et al., 2002). Interestingly, heredity of relative proportions of skeletal
muscle fiber types is considered to be between 40% and 50% (Simoneau & Bouchard, 1995).
These and studies similar to them will initiate more research into the area of human performance
genetics in order to discover favorable blend of genes, that are conducive to an athleteís specific
discipline (e.g. sprinting or endurance running).
Candidate genes in elite athletes (ACE I/D and ACTN3 R577X polymorphisms)
Specific allelic variants of the ACE and ACTN3 genes are known to produce favorable
traits with respect to athletic performance. These two genes were chosen, based on current
literature references, because they have opposing effects in the human body; variants of the ACE
gene are assumed to express bigger advantage in endurance activities, whereas, variants of the
ACTN3 gene are considered to present an advantage to power athletes, who require short surge
of intense strength and power.
ACE I/D polymorphism
Because endurance performance is a multifactorial trait, the list of candidate genes which
could account for human variation in related phenotypes is extensive. One of the first
characterized and most frequently studied genetic variant is a polymorphism in the angiotensin
converting enzyme I gene (ACE) (MacArthur & North, 2005). Specific allelic variants of the
ACE gene are known to produce favorable traits with respect to athletic performance. ACE is a
Exercise genomics
part of renin-angiotensin system which represents a hormonal cascade that regulates
cardiovascular function (Baudin, 2002). This pathway starts with the production of renin, in
kidneys, which transforms inactive angiotensinogen to angiotensin I. Second step is related to the
effect of ACE on angiotensin I and the result is generation of biologically active angiotensin II,
which is a strong vasoconstrictor and, in addition, it stimulates renal sodium reabsorption and
aldosterone production (Pescatello et al., 2006). A functional polymorphism of gene that codes
ACE is the insertion (I) and deletion (D) polymorphism which depends on the presence or
absence of a 287 amino acid base pairs on autosomal chromosome 17 (Pescatello et al., 2006).
This variation has given three ACE ID genotypes: II, ID and DD and their distributions in a
white people population are approximately 25% for II, 50% for ID and 25% for DD genotype
(Barley, Blackwood & Carter, 1994). The D allele of this polymorphism is related to higher
serum and tissue ACE activity which can result in greater production of angiotensin II and
aldosterone as well, increased sodium reabsorption and increased vascular smooth muscle
growth (Williams et al., 2005; Williams et al., 2004; Myerson et al., 1999). This allele is more
common in muscle strength and power athletes and it is associated with a superior muscle size
and strength response to exercise training (Hagberg et al., 1998; Montgomery et al., 1999). The I
allele is more present in endurance athletes, such as distance runners, rowers and mountaineers
and is associated with a prolonged cardiovascular response to endurance training. Lower ACE
activity in both serum and tissues is present in people with the I allele compared to the D allele
(Danser et al.,
1995; Rigat et al.,
1990). Several other studies have shown a significant
association between ACE genotype and elite athlete status. Montgomery et al. reported an
increased frequency of the I allele in 25 British mountaineers compared to 1906 sedentary
controls (Montgomery et al., 1998). On the other hand, higher frequency of the D allele was
found in 35 elite short-distance swimmers and such findings suggested that these two alleles of
ACE I/D polymorphism have dissimilar effects on performances of elite athletes (Woods et al.,
2001). On the contrary, Rankinen and coworkers (2000) published results of 192 males elite
endurance athletes compared with
189 sedentary controls and there was no difference in
genotype frequencies between these two groups. In addition, one more study has shown the lack
of physiological explanation for any association between the endurance-related cardiorespiratory
phenotypes and the ACE polymorphisms. In summary, data from the HERITAGE Family Study
do not support the concept that genetic variation at the ACE locus is a major contributor to the
cardiorespiratory endurance-related phenotypes in the sedentary state in healthy Caucasian
people (Rankinen et al., 2000).
Relation of genetic variants of ACE gene with athletic performance
Several mechanisms could explain how ACE expression might influence athletic
performance. Generally, cardiorespiratory function, with maximal oxygen uptake which is a
solid predictor of endurance performance, is related to the effect of ACE genotype. As
previously mentioned, a person with the I allele has reduced ACE serum and tissue levels and its
activity. This allele is thought to be a favorable mutation because lower ACE activity leads to
less vasoconstriction and thus an increased delivery of oxygenated blood to the working muscles.
Moreover, individuals with the I allele or the II (homozygote) genotype have greater advantage
in endurance activities, such as running, cycling, and swimming, where demand for oxygen is
crucial. A feasible explication for such findings comes from a study by Zhang and coworkers,
who showed that the ACE I allele is related with higher mass of type I (slow twitch) muscle
fibers in a person (Zhang et al., 2003). Slow twitch fibers acquire energy for their metabolism
from aerobic sources and they are fatigue-resistant at relatively low velocities of contraction. On
the other hand, the D allele is associated with the expression of type IIa and IIb (fast twitch)
fibers which are more efficient in power and strength performance and less fatigue resistant.
Nonetheless, there is some contradictory evidence regarding the effect of the ACE gene on
endurance and power performance. In some studies, researchers have shown that in older adults
V. Gali
there was no association between ACE gene and physical characteristics as yet (Rankinen et al.,
2000; Frederiksen et al., 2003).
In spite of all confusing results, the ACE gene continues to be the most extensively
studied of any gene related to athletic performance, with huge amount of articles examining the
effect of I/D polymorphism on fitness and performance features. The opposite findings amid
many studies illustrate the complexity of genetic studies of complex characteristics. Literature
results must be observed thoroughly before one can certainly conclude about the effect of ACE
variations on performance phenotypes. For a research to be successful, it is of the utmost
importance to have collaborative effort through data sharing among multicenter research
ACTN3 R577X polymorphism
The ACTN3 gene and is nonsense R577X polymorphism has generated noticeable
interest in the past few years. This is the first structural skeletal muscle gene with a relation
between its genotype and elite sprinterí performance (MacArthur & North, 2007; Yang et al.,
2003). The alpha-actinins are a family of actin-binding proteins which play a main role in the
maintenance and regulation of the cytoskeleton inside a muscle fiber (Blanchard et al., 1989). In
mammals, there are four alpha-actinins. Skeletal muscle has highly expressed alpha-actinin-2
and alpha-actinin-3 as major structural parts of the contractile elements at the Z-line, which is an
important structure within the sarcomere and its function is to provide structural support for the
transmission of force when the muscle fibers are activated. (Virel & Backman, 2004; Dixson et
al., 2003; Beggs, Byers & Knoll, 1992). The function of alpha-actinins is to connect with actin
filaments, sustain the order of myofilaments and coordinate myofilament contraction by
stabilizing the contractile apparatus (Yang et al., 2003). Alpha-actinin-3 is expressed only in fast
glycolytic skeletal muscle fibers (Mills, Yang & Weinberger, 2001). Researchers believe that
alpha-actinin-3 may be optimized in order to decrease the damage which could be induced by
eccentric muscular contractions (Yang et. al, 2003). This is extremely important during forceful
contractions, which are abundant in fast twitch muscle fibers. Astonishingly, an estimated one
billion humans worldwide are completely deficient in alpha-actinin-3, because of homozygosity
for a common nonsense polymorphism (R577X) in the ACTN3 gene (MacArthur et al., 2007;
North et al., 1999). The absence of this protein is not related to a disease phenotype, since other
proteins can counterbalance, although not completely, its lack in fast twitch skeletal muscle
fibers. Moreover, the absence of this protein structure in skeletal muscles has been suggested to
block the performance of fast twitch fibers, which are important for rapid, powerful contractions.
A usual genetic variation in the ACTN3 gene results in the replacement of an arginine
(R) with a stop codon (X) at amino acid 577 (R577X). The R577 allele is the normal allele with
functional alpha-actinin-3, whilst the 577X allele has an amino acid sequence change which
produce nonfunctional protein alpha-actinin-3. This polymorphism results in the XX, RX and
RR genotype. Representation among healthy white subjects is 18, 52 and 30%, respectively
(Yang et al., 2003). It has been noticed that the recurrence of the ACTN3 577RR genotype was
higher among elite sprinters when comparing with endurance runners or control participants
(Niemi & Majamaa, 2005). This finding can suggest that the presence of 577RR allele might
have a beneficial effect on skeletal muscle function during powerful contractions.
According to the literature suggestions, that alpha-actinin-3 performs important functions
in fast twitch muscle fibers, it was expected to predict that there might be fine differences in
skeletal muscle function among humans with different ACTN3 R577X genotype. Two alleles of
ACTN3 gene may provide usefulness for different type of muscle performance. The R allele,
which generates a functional alpha-actinin-3 protein, appears to favor strong muscle contraction,
while on the other hand, the X allele might somehow provide advantage for slow and efficient
muscle performance.
Exercise genomics
Future perspectives and research activities
During last two decades, an increasing level of competition in different sports has caused
athletes to strive to sport results and success at no cost. Studies of the importance of genomic
factors in the responses and adaptations of performance and health-related traits to exercise have
increased during period of last 10 years (Bouchard et al., 2008). Unfortunately, along with recent
developments in gene manipulation, there is a growing concern that researchers and elite athletes
could be able to abuse this innovative technology in order to ìengineerî individuals who could
permanently express desirable genes for a peak athletic performance. Moreover, everyone is
worried that ìgene dopingî would become a reality one day and, as a result, sports competitions
could lose their true meaning and significance among athletes. However, successful
identification of genes, which control physical performance characteristics, could benefit
researchers to determine whether an athleteís genotype has been artificially changed in order to
express advantageous genotypes with increased endurance capabilities or muscular strength.
Furthermore, the process of supreme talent identification could be possible by the
discovery of genetic variants which has strong effect on athletic performance. A routine genetic
analysis could be added to the existing set of physiological, biochemical and psychological tests
which are the current basis for selecting skillful young athletes for further training. However,
there is still no solid evidence that any of these variants have predictive value for prospectively
identifying potential elite athletes. Only relying on large and prospective cohort studies,
researchers could be able to evaluate the true values of genetic testing. Several genetic factors,
for which positive associations have been reported in elite athlete cohorts (including the ACE
I/D and the ACTN3 R577X polymorphisms), are not sufficient to tell if someone can become an
elite athlete. However, genomic factors may influence in which sport an elite athlete can
compete successfully. In the case of ACE and ACTN3, one allele combination appears to favor
performance in sprint or power events (the ACE D and ACTN3 R allele), whereas the other
benefit the ability to strive in endurance sports (the ACE I and ACTN3 X allele). This can lead to
conclusion that some genetic factors might not be useful in predicting if a young, amateur athlete
has elite potential. On the contrary, it may help to guide the choices of young athletes and their
coaches in determining appropriate event and training which would be best suited for them.
Nevertheless, current genetic testing cannot provide an extra advantage over existing
testing methods in determining sports selection in young athletes. The main challenge still
remains to identify other, complex polygenetic variants and their interactions with environmental
factors which could provide benefit in the sports selection and existing talent identification.
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Submitted 12 April, 2011
Accepted 20 May, 2011