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ACTN3 Genotype in Professional Endurance

Cyclists

Article in International Journal of Sports Medicine · November 2006

DOI: 10.1055/s-2006-923862 · Source: PubMed

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A. Lucia1
F. Gómez-Gallego1
C. Santiago1
F. BandrØs1
C. Earnest2
M. Rabadµn3
J. M. Alonso4
J. Hoyos5
A. Córdova6
G. Villa7
C. Foster8 ACTN3 Genotype in Professional Endurance Cyclists

Physiology & Biochemistry

Abstract
The Z-disk protein a-actinin-3 is only expressed in type II muscle
fibres, which are responsible for generating forceful contractions
at high velocity. Despite the evolutionary conservation of a-ac-
tinin-3, approximately one in every five Caucasians of European
ancestry is totally deficient in this protein, due to homozygosity
for a R577X polymorphism in the ACTN3 gene. This, together
with the results of recent research on elite athletes, suggests that
the ªnullº XX polymorphism might confer some advantage to en-
durance performance events. To test this hypothesis, we studied
the frequency distribution of R577X genotypes in a group of 50
top-level male professional cyclists (26.9  0.4 yrs [mean  SEM];
VÇO2max: 73.5  0.8 ml ´ kg±1 ´ min±1). Their results were compared
with those of a group of 52 Olympic-class male endurance run-
ners (26.8  0.6 yrs; VÇO2max: 73.3  0.8 ml ´ kg±1 ´ min±1) and 123
healthy, sedentary male controls. All subjects were Caucasian,
and of European ancestry. No significant differences (p > 0.05)
were found between groups: RR: 28.5 %; RX: 53.6 % and XX:
17.9 % in controls; RR: 28.0 %; RX: 46.0 % and XX: 26.0 % in cyclists;
and RR: 25.0%; RX: 57.7 %; XX: 17.3 % in runners). No differences
were found in indices of endurance performance (VO2peak or ven-
tilatory thresholds) between athlete carriers of each R577X gen-
otype. In summary, although the a-actinin-3 deficient XX geno-
type may be detrimental for sprint performance in humans, the
R577X polymorphism of the ACTN3 gene does not appear to con-
fer an advantage on the ability of male athletes to sustain ex-
treme endurance performance.
Key words
a-actinin-3 ´ polymorphism ´ gene ´ runners

Introduction expression of the two isoforms has diverged through mammali-

The two sarcomeric a-actinin isoforms in humans, a-actinin-2
and a-actinin-3, are acting-binding proteins that constitute the
predominant component of the Z-disk [15]. Besides their me-
chanical role, both proteins interact with proteins involved in nu-
merous signalling and metabolic pathways [10]. The pattern of
an evolution, with a-actinin-2 being expressed in skeletal
muscle fibres and cardiomyocites, while the expression of a-ac-
tinin-3 is almost exclusively restricted to fast, glycolytic type II
muscle fibres [10,12], which are responsible for generating force-
ful contractions at high velocity [10].

Affiliation
1
European University of Madrid, Madrid, Spain
2
Cooper Institute Center for Human Performance and Nutrition Research, Dallas, Texas, USA
3
Department of Physiology, Sport Medicine Center, Higher Sports Council, Madrid, Spain
4
Medical Department, Spanish Track and Field Federation, Madrid, Spain
5
Professional cycling team Isles Baleares, Baleares, Spain
6
Department of Biochemistry and Physiology, University of Valladolid, ncity?, Spain
7
Departamento de Physical Education, University of León, ncity?, Spain
8
Department of Exercise and Sport Science, University of Wisconsin-La Crosse, La Crosse, WI, USA

Correspondence
Alejandro Lucía, MD PhD ´ European University of Madrid ´ nStreet? ´ 28670 Madrid ´ Spain ´
Fax: 34 91616 82 65 ´ E-mail: alejandro.lucia@uem.es

Accepted after revision: December 1, 2005

Bibliography
Int J Sports Med 2006; 27: 1 ± 5  Georg Thieme Verlag KG ´ Stuttgart ´ New York ´
DOI 10.1055/s-2006-923862 ´
ISSN 0172-4622

Despite the evolutionary conservation of a-actinin-3, a signifi-
cant proportion of healthy individuals (e.g., ~ 18 % of Caucasians
of European ancestry) are totally deficient in this protein as they
are homozygous for a premature stop codon polymorphism
(577X) in the gene (ACTN3) encoding for a-actinin-3 [12]. This
genetic variation is associated with no known disease pheno-
type. The frequency of the 577X (or simply ªXº) allele has, in fact,
been shown to be significantly higher in Australian female en-
durance athletes as opposed to sprint/power athletes of the same
ethnic origin [17]. In addition, the frequency of homozygotes for
the X allele was higher in Finnish endurance athletes (n = 52)
compared to sprinters (n = 89); and none of the sprinters were
XX genotype [13]. In a recent study with non-athletes, Clarkson
et al. [2] found that women homozygous for the X allele had the
Physiology & Biochemistry
lowest baseline strength.
The higher frequency of the X allele in some cohorts of elite en-
durance athletes [13,17] raises the possibility that total defi-
ciency of alpha-actinin 3 may, in fact, confer some beneficial ef-
fect to endurance performance. In this regard, professional cy-
clists able to successfully complete one of the three classical cy-
cling tour races (Tour de France, Giro dItalia and Vuelta a Espaæa)
represent an excellent model to further study this question.
Three-week cycling tour races provide arguably the single most
unique model of extreme, unremitting endurance exercise un-
dertaken by humans. Especially remarkable to these events is
that: 1) they are composed of 20 ± 22 daily stages or ªsub-racesº
of ~ 5 h duration, with only ~ 18 h separating each stage, and 2)
the magnitude of relative energy expenditure is extremely high,
i.e. 1.5 to 3 times higher than that of other endurance athletes
(such as runners) during training over the same time period,
and ~ 2 times the exercise load estimated for human hunter-
2 gatherers [4]. As such, it might be hypothesised that these ath-
letes might have been selected to have a unique distribution of
ACTN3 genotypes. It was therefore the purpose of this investiga-
tion to study the frequency distribution of ACTN3 genotypes in a
group of top-level professional cyclists able to successfully com-
plete one or more of the classical three-week tour races. Their re-
sults were compared with those of elite endurance runners and
sedentary controls. Based on the findings of recent studies
[13,17], we hypothesised that the proportion of subjects homo-
zygous for the X allele and the frequency of this allele would be
greater in cyclists than in controls or other elite endurance ath-
letes (i.e., runners) not engaging in ultra-endurance events.
Methods
Subjects
Written consent was obtained from each subject. The study pro-
tocol was approved by the institutional ethics committee (Uni-
versidad Europea de Madrid, Spain) and was in accordance with
the Declaration of Helsinki for Human Research.
The sample was comprised of 102 Caucasian, of European ances-
try, elite endurance athletes (i.e., 50 unrelated top-level cyclists
[age: 26.9  0.4 yrs; height: 178.0  0.8 cm; mass: 67.4  0.9 kg]).
They were from the four best Spanish professional cycling teams
and ranked amongst the top 65 ± 70 Spanish cyclists in terms of
three-week stage race performance. The sample also included 52
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runners (age: 26.8  0.6 yrs; height: 175.0  0.9 cm; mass: 61.6 
0.9 kg) who were the best Olympic-class Spanish male runners
(specialists in middle-distance events [1500 m], 5000/10 000 m
track races, 3000 m steeple chase events or marathon) based on
performance during international competitions for the 1999 ±
2005 period. ªOlympic classº was defined as ªhaving participated
in one or more Olympic Games or being enrolled in the special
program funded by the Spanish government for athletes training
to participate in the Olympics.º
We specifically chose professional cyclists for this study who met
the following criteria: 1) being employed by a professional cy-
cling team, 2) having at least 2 years experience in the profes-
sional category of the International Cycling Union (ICU), and 3)
had finished one or more of the classic three-week stage races
between 1999 to 2004. During this period, eleven of the cyclists
won at least one mass-start stage or time trial of the Tour, Giro or
Vuelta, and seven and eleven were among top-3 and top-10 fin-
ishers, respectively, in one of these three-week races. No cyclist
was a pure sprinter (a specialist in the final sprint of mass-start
stages, which demands very fast, powerful muscle contractions
comparable to those of sprint events in track and field competi-
tions).
All of the runners participate in cross-country races (usual dis-
tance of 10 000 ± 12 000 m) during winter months (including
world cross-country championships for some of them). Irrespec-
tive of their speciality, the training loads of the 52 runners typi-
cally included more than 150 km ´ wk±1 (150 ± 200 km ´ wk±1) and
approached 250 km ´ wk±1 in marathoners during some periods
of the year. Achievements among the runners included: Euro-
pean champion (1500 m, 3000 m steeple chase, 5000 m or mara-
thon), World champion and top-3 in World championships (e.g.,
Marathon, 1500 m, or 3000 m steeple chase), or Olympic medal-
list and finalist in Olympic Games (1500 m, 3000 m steeple-
chase, 5000 m, 10 000 m or Marathon).
A group of 123 healthy, sedentary, unrelated, male Caucasians, of
European descent, aged 19 ± 50 years served as controls.
Determination of indices of endurance performance
During 2001, we measured the gas-exchange of each athlete dur-
ing exercise tests to fatigue using open circuit spirometry with
continuous, breath-by-breath monitoring (Oxycon Champion
System, Jaeger, Wuerzburg, Germany). The cyclists and runners
were evaluated while pedalling on a cycle-ergometer (Ergomet-
rics 900, Ergo-line, Bitz, Germany) or running on a treadmill
(Technogym Run Race 1400 HC, Gambettola, Italy) respectively,
following an incremental protocol (i.e., workload increases of
25 W ´ min±1 starting at 25 W for the cyclists and of 1 km ´ h±1
starting at 8 km ´ h±1 [with constant 1% upgrade] for the runners).
The following variables were measured during each test: oxygen
uptake (VÇO2), pulmonary ventilation (VÇE), ventilatory equivalent
for oxygen (VÇE ´ VÇO2±1) and carbon dioxide (VÇE ´ VÇCO2±1), and end-
tidal partial pressure of oxygen (PETO2) and carbon dioxide (PET-
CO2).
Maximal oxygen uptake (VÇO2max) was recorded as the highest
VÇO2 value obtained for any continuous 1-min period during the
tests. At least two of the following criteria were also required

for the attainment of VÇO2max: a plateau in VÇO2 values despite in-
creasing workload, a respiratory exchange ratio ³ 1.15 or the at-
tainment of a maximal heart rate (HRmax) above 95% of the age-
predicted maximum. The ventilatory threshold (VT) was deter-
mined using the criteria of an increase in both VÇE ´ VÇO2±1and
PETO2 with no increase in VÇE ´ VÇCO2±1 whereas the respiratory
compensation threshold (RCT) was determined using the criteria
of an increase in both VÇE ´ VÇO2±1 and VÇE ´ VÇCO2±1 and a decrease in
PETCO2 [8]. Two independent observers detected VT and RCT. If
there was disagreement, the opinion of a third investigator was
obtained [8].
Genotype determinations
DNA purification
Genomic DNA was extracted from peripheral EDTA treated anti-
coagulated blood obtained according to standard phenol/chloro-
form procedures followed by alcohol precipitation.
DNA amplification
The polymerase chain reaction (PCR) was performed in order to
amplify the sequence containing the mutation. A fragment of
303 bp was amplified with the following primers: ACTN3-F 5¢-
CTG TTG CCT GTG GTA AGT GGG labelled a 5¢ with VIC and
ACTN3-R 5¢- TGG TCA CAG TAT GCA GGA GGG [12]. The PCR con-
ditions were as follows: initial denaturing at 95 8C 5 min; 35
cycles at 95 8C 30 s, 60 8C 30 s, 72 8C 30 s and a final extension at
72 8C 10 min.
Polymorphism identification
ACTN3 genotypes were established by enzymatic digestion of
amplicons with Dde I [12]. The R577X change creates a restric-
tion site resulting fragments of 108, 97 and 86 bp. Digestion of
R577 allele resulting fragments of 205 and 86 pb.
Digestion products (108 bp for 577X and 205 bp for R577) were
detected by capillary electrophoresis in an ABI Prism 310 genetic
analyser (nmanufacturer information?n).
Statistical analysis
Allele and genotype frequencies of the R577X polymorphism in
the ACTN3 gene were compared among the three groups using a
c2-test. One-way analysis of variance (ANOVA) was used to com-
pare laboratory indices of endurance performance (VÇO2max, VT
and RCT) between the three genotypes (RR, RX and XX) within
each group of cyclists and runners, respectively. The ScheffØ test
was applied post hoc. The level of significance was set at 0.05.
Demographic and physiological data (VÇO2max, VT and RCT) are
presented as mean  SEM.
Results
ACTN3 genotype distribution was in agreement with Hardy-
Weinberg equilibrium within each of the three groups (controls:
c2(1) = 0.895; p = 0.344; cyclists: c2(1) = 0.317; p = 0.573; and run-
ners: c2(1) = 1.343; p = 0.247). The frequency of the X allele and of
the a-actinin-3 deficient XX genotype in our control group
(44.7 % and 17.9 %, respectively) was comparable to the distribu-
tion reported in the literature for healthy male Caucasians
[12,14]. The genotype distribution of the ACTN3 gene did not sig-
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Fig. 1 Frequency distributions of the genotype for the R577X poly-
morphism of the ACTN3 gene in controls (n = 123), runners (n = 52)
Physiology & Biochemistry
and cyclists (n = 50). No significant differences existed between
groups.
nificantly differ (c2(4) = 2.22; p = 0.695) among the three groups
of study (RR: 28.5 %; RX: 53.6 % and XX: 17.9 % in controls; RR:
28.0 %; RX: 46.0 % and XX: 26.0% in cyclists; and RR: 25.0 %; RX:
57.7 %; XX: 17.3 % in runners) (Fig. 1). Similarly, the distribution
frequency of the R and X alleles was similar in the three groups
(c2(2) = 0.65; p = 0.724) (R: 55.3 %; X: 44.7 % in controls; R: 51.0 %;
X: 49.0 in cyclists; and R: 53.9 %; X: 46.1% in runners). Interest-
ingly, all three genotypes (RX, XX and RR) were present in the
seven cyclists who have finished at least one edition of the Tour,
Vuelta and/or Giro in a top-3 position in the last years.
The VÇO2max of cyclists and runners averaged 73.5  0.8 and
73.3  0.8 ml ´ kg±1 ´ min±1, respectively. Their VT and RCT corre-
sponded to 69.5  1.0% and 86.9  0.7% of VÇO2max, (cyclists) and
69.0  1.0% and 88.2  0.7% of VÇO2max, (runners). No significant 3
differences were found in VÇO2max, VT and RCT between the three
genotypes (RR, RX and XX) within each group of cyclists and run-
ners (Table 1). Similarly, no significant differences were found
among the three genotypes in these indices when combining cy-
clists and runners as a single group.
Discussion
This is the first study to determine the genotype distribution of
the R577X polymorphism in the ACTN3 gene among professional
cyclists able to succeed in three-week races. This unique cohort
provides an excellent model to determine if deficiency of a-ac-
tinin-3 (i.e., homozygosity for the X allele) is of benefit for ex-
treme endurance events. Although approximately one in every
four cyclists (26 %) was totally deficient in this protein, this result
did not reach statistical significance, which is in contrast with
our hypothesis. Indeed, approximately one in every five controls
and Olympic-class endurance runners were also homozygous for
the X allele (17.9 % and 17.3% of their respective cohorts). Simi-
larly, the frequency of the X allele did not vary among the three
groups of study. These results, together with the fact that no dif-
ferences were encountered in well accepted indices of endurance
performance (VÇO2max, VT and RCT) [11] among ACTN3 genotypes
indicate that, despite its relatively high occurrence among cy-
clists, deficiency of a-actinin-3 in working muscles does not
necessarily confer a performance benefit in ultra-endurance
Lucia A et al. ACTN3 Genotype in Cyclists¼ Int J Sports Med 2006; 27: 1 ± 5

Table 1 Main characteristics (mean  SEM) of cyclists and runners according to their genotype for the R577X polymorphism in the ACTN3 gene
RR
Cyclists (n = 13)
Age (yrs) 26.8  1.0
Height (cm) 179.2  1.5
Mass (kg) 69.4  1.8
VÇO2max (ml ´ kg±1 ´ min±1) 75.4  1.7
Runners (n = 13)
Age (yrs) 28.1  1.2
Height (cm) 172.3  1.7
Physiology & Biochemistry
Mass (kg) 59.0  2.1
VÇO2max (ml ´ kg±1 ´ min±1) 75.2  2.1
ÇO2max (maximal oxygen uptake). No significant differences were found between means (p > 0.05)
Abbreviations: V
events, at least in males. In contrast, there is increasing support
for an association between sprint performance in both sexes and
ACTN3 genotypes, with the lack of a-actinin-3 being detrimental
[13,17].
Our groups had small sample sizes, which decreases the statisti-
cal power of comparisons. Nevertheless, the two athletes groups
were very homogenous in terms of performance as we examined
the Worlds top-level competitors from the same country partic-
ipating in a single sport. Furthermore, the runners that we exam-
ined are Olympic-class runners, many of which are currently the
best non-Africans in cross-country and track (1500 m, 3000 m
4 steeplechase, 5000 m and 10 000 m, or marathon). Based on the
results of annual competition records in track and field from the
International Association of Athletics Federation (IAAF), we can
safely estimate that there are currently no more than 65 ± 70
non-African runners in the World with such a high competition
level. The same consideration applies to our group of cyclists as
they have solid experience in three-week races and there are cur-
rently no more than 100 cyclists in the World capable of this
competition level. Another potential limitation comes from the
fact that we did not corroborate our findings in a group of female
athletes, e.g. female cyclists participating in tour races. Pioneer-
ing research [17] has indeed reported significantly higher fre-
quency distribution of the XX genotype in female endurance ath-
letes than in controls [17]. In this regard, it has been hypothe-
sised that ACTN3 genotype could have a proportionally smaller
effect in men than women [2]. MacArthur and North have sug-
gested that the lower average levels of testosterone in female
athletes (i.e., compared to men) could increase the influence that
the variations in some biological parameters (e.g., variations in
ACTN3 genotype) have on athletic performance [10].
The presence of a-actinin-3 may have a beneficial effect on the
function of skeletal muscle in generating forceful contractions
at high velocity, and hence provide an evolutionary advantage
because of increased sprint performance, whereas the X allele,
and particularly the XX genotype, may favour slow, efficient
muscle performance [10]. In this regard, muscle efficiency
(which is positively associated with the proportion of type I fi-
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RX XX
(n = 23) (n = 14)
26.8  0.5 27.3  0.6
177.7  1.2 177.6  1.6
67.7  1.3 64.7  1.5
71.8  1.0 74.3  1.4
(n = 30) (n = 9)
26.9  0.9 24.4  1.2
175.9  1.1 176.0  2.4
62.3  5.6 63.3  1.8
73.3  1.0 70.8  1.6
bres [3], i.e., expressing no a-actinin-3) and the ability to save
as much energy as possible during each daily stage are crucial
to the ability to complete three-week races [7]. Nevertheless,
the physiological demands of modern three-week tour races are
so high that cyclists are also required to perform very forceful leg
muscle contractions during the competitively critical phases of
the race despite the long duration of these events [9]. In recent
years, the ability to produce high power outputs (i.e., well above
400 W) during long periods (> 20 min) is a key performance de-
terminant. Despite the long duration of daily stages (~ 5 hours on
average), professional cycling has evolved into a power-oriented
sport over the past several years, at least as far as the most crit-
ical phases of competitions (mountain ascents and time trials)
are concerned. For instance, to maintain a power output of
400 W at a mean pedalling cadence of 70 rpm, riders must gener-
ate a force of ~ 500 N for every leg muscle contraction [9]. On the
other hand, although running efficiency is also crucial in endur-
ance running competitions (in fact, the superiority of East Afri-
can runners is largely attributable to their higher economy com-
pared to Caucasian athletes) and some investigations have found
that improved running economy is associated with a higher pro-
portion of type I fibres (again, expressing no a-actinin-3
[1, 5,16]), body mass and shape (especially of the legs) play a
more important role [6]. In fact, the percentage distribution of
the a-actinin-3 deficient XX genotype is of only 11% and 1% in
elite Ethiopian and Kenyan elite endurance runners, respectively,
and does not differ from that of their respective controls [18]. In
line with these recent findings with East-African runners, the
percentage distribution of the XX genotype did not differ be-
tween the Olympic-class runners studied here (many of whom
are the best Caucasian runners in the World) and their Caucasian
controls. Further, the very high speeds and near-maximal inten-
sities at which endurance events are currently performed by top-
level runners probably requires the ability to recruit type II fi-
bres, i.e., expressing a-actinin-3. For instance, contemporary
running velocities in 5000 and 10 000 m events are such that
more and more top-level distance runners are able to run
1500 m in less than 3 min 35 s.

In summary, although the a-actinin-3 deficient XX genotype ap-
pears to be detrimental for sprint performance in humans (as
this Z-disk structural protein is only expressed in type II fibres),
ACTN3 genotypes do not appear to influence human extreme en-
durance performance, of which cycling three-week tours is per-
haps the best possible example. Our data demonstrate that cy-
clists both with or without a-actinin-3 in their working muscles
can reach top-level endurance performance in their event, as
both possibilities might present some advantages for endurance
cyclists, e.g., increased muscle efficiency in a-actinin-3 deficient
subjects or the ability to produce high power outputs in those ex-
pressing this muscle protein. Finally, there appears to exist a
trend towards a higher frequency of the XX genotype in cyclists
although statistical significance was not reached in our study.
Future studies using larger cohorts or professional cyclists or
other ultra-endurance athletes would clarify this issue.
Acknowledgements
We are indebted to Prof. Kathryn North for invaluable discussion
of our data. This study was supported by a grant from Consejo
Superior de Deportes (02/UPR10/04).
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