ISSN: 0301-4460 (print), 1464-5033 (electronic) Ann Hum Biol, Early Online: 1–6 ! 2015 Informa UK Ltd. DOI: 10.3109/03014460.2015.1050065


The genetics of human running: ACTN3 polymorphism as an evolutionary tool improving the energy economy during locomotion Leonardo A. Pasqua1, Saloma˜o Bueno1, Monique Matsuda2, Moˆnica V. Marquezini3, Adriano E. Lima-Silva4, Paulo H. N. Saldiva3 and Roˆmulo Bertuzzi1,4 Endurance Performance Research Group (GEDAE-USP), School of Physical Education and Sport, 2Faculty of Medicine, 3Laboratory of Experimental Air Pollution, Department of Pathology, Faculty of Medicine, University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil, and 4Sport Science Research Group, Department of Physical Education and Sports Science (CAV), Federal University of Pernambuco, Vito´ria de Santo Anta˜o, PE, Brazil

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Background: Covering long distances was an important trait to human evolution and continues to be highlighted for health and athletic status. This ability is benefitted by a low cost of locomotion (CoL), meaning that the individuals who are able to expend less energy would be able to cover longer distances. The CoL has been shown to be influenced by distinct and even ‘opposite’ factors, such as physiological and muscular characteristics, which are genetically inherited. In this way, DNA alterations could be important determinants of the characteristics associated with the CoL. A polymorphism in the ACTN3 gene (R577X) has been related to physical performance, associating the X allele with endurance and the R allele with strength/ power abilities. Aim: To investigate the influence of ACTN3 genotypes on the CoL. Subjects and methods: One hundred and fifty healthy male individuals performed two constant speed tests (at 10 and 12 km/h) to determine the CoL. Results: Interestingly, the results showed that heterozygous individuals (RX genotype) presented significantly lower CoL compared to RR and XX individuals. Conclusions: It is argued that RX genotype might generate an intermediate strengthto-endurance phenotype, leading to a better phenotypic profile for energy economy during running and, consequently, for long-term locomotion.

ACTN3, evolution, genetics, human locomotion, polymorphism

Introduction Recent findings have suggested that endurance ability is an important trait in human evolution (Bramble & Lieberman, 2004). During the development of the modern Homo sapiens, singular adaptations to endurance running were reached, which were particularly important to the conquest of almost the entire world (Mattson, 2012). More efficient locomotion resulted in humankind abandoning the sedentary lifestyle, spreading over the continents and the most diverse environments and adopting practices such as persistence hunting to survive (Steudel-Numbers & Wall-Scheffler, 2009). Thus, the cost of locomotion (CoL) has been stated as an important trait in the evolution of humans and their spread across the Earth. In fact, with a lower energy expenditure and a higher heat dissipation (Fletcher et al., 2011), early humans were able to improve their performance during hunting practices and

Correspondence: Leonardo A. Pasqua, Endurance Performance Research Group, School of Physical Education and Sport, University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil. Tel: 55 11 98775-5719. Fax: 55 11 3813-5091. Email: [email protected]

History Received 11 September 2014 Revised 26 January 2015 Accepted 5 May 2015 Published online 6 July 2015

journeys to distant locations, particularly in hot temperatures (Liebenberg, 2008). It has been hypothesised that the CoL may be influenced by distinct and even ‘opposite’ mechanisms, such as physiological parameters and muscle strength (Saunders et al., 2004). There is also an important interaction between environmental and genetic factors influencing CoL. Through the Darwinian Theory of Evolution, it is now understood that long-term acquired traits in the evolution of different species are firstly triggered by environmental conditions, leading to the selection of the most adapted individuals. The characteristics of these selected individuals are genetically inherited, thus generating a more evolved species. In this way, the genetic component contained in the DNA molecule is an important factor in evolution (Fu & Akey, 2013). Thus, it is possible that genetic components are also responsible for the development of the efficiency of energy consumption in humans. These characteristics provide humans with highlighted adaptation and development, enabling some important practices, such as persistence hunting, which developed in parallel to human endurance capacity (Liebenberg, 2008; Lieberman, 2015).

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L. A. Pasqua et al.

Recent investigations have shown that DNA polymorphisms, which are defined as alterations in the nucleotide sequence in the DNA molecule (Breckpot et al., 2011), have emerged as important tools in the evolution of humans. In this way, ‘positive’ polymorphisms have been selected throughout human history, leading to adaptation to distinct environments (Fu & Akey, 2013). Regarding the energetic metabolism, an important polymorphism is the ACTN3 R577X polymorphism. This polymorphism promotes an arginine (R) to premature stop codon (X) change in the 577 residue (North et al., 1999), resulting in a complete absence of the protein -actinin-3 in type II muscle fibres of muscle tissue in individuals carrying the XX genotype. This absence might have two distinct consequences. First, it has been demonstrated that -actinin-3 absence induces metabolic changes towards oxidative metabolism, resulting in higher activity of oxidative enzymes (e.g. citrate synthase) and lower activity of glycolytic enzymes (e.g. lactate dehydrogenase and glycogen phosphorylase) (Macarthur et al., 2007; Quinlan et al., 2010). Because of this, it has been observed that XX individuals are over-represented among long-distance athletes (Yang et al., 2003). Second, it has been observed that the presence of -actinin-3 leads to an increased force generation, increased fast fibre diameter and higher strength capacity (Macarthur et al., 2008). In this way, RR individuals are over-represented among power-oriented athletes (Druzhevskaya et al., 2008). Collectively, these results indicate that X and R alleles of the ACTN3 R577X polymorphism could lead to opposite phenotypes, resulting in advantages in activities presenting distinct characteristics. There are, however, special circumstances or traits where both strength and endurance-related phenotypes are needed equally, in particular when considering CoL. It has been stated that energy expenditure during running is dependent on several physiological and muscular factors (Saunders et al., 2004). Thomas et al. (1999) observed an improved CoL after a 5 km race, which was correlated with increased ventilation during exercise (r ¼ 0.64; p50.05). This suggests that the enhancement in metabolic cost from augmented circulation, VE and sweating, can influence the CoL. Additionally, Storen et al. (2008) observed a significant (5%) decrement in CoL after 8 weeks of strength training. The reduced CoL after strength training may have been due to either a lower number of recruited motor units and lower applied force per stride cycle relative to their maximum strength (Ronnestad & Mujika, 2014), or a higher ability to store and restitute the elastic energy, providing an additional non-metabolic source of energy (Arampatzis et al., 2006), or both. As suggested by Garland et al. (1990), there may be a ‘tradeoff’ between strength/power and endurance characteristics in the evolution process. Regarding the ACTN3 gene, it is possible to suggest that the RX genotype could intermediate this ‘trade-off’, since it provides a positive allele to endurance (i.e. X allele) and a positive allele to muscle strength (i.e. R allele). With this reasoning, it is attractive to suggest that the ACTN3 RX genotype might be the optimal genotype for an optimised CoL. Therefore, considering the opposite factors able to influence energy expenditure during locomotion, it is attractive to investigate the influence of genetic factors on CoL. Thus, the aim of the present study was to verify if the CoL

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would be different between individuals with different ACTN3 genotypes.

Methods This experimental protocol was approved by the ethics committee of the School of Physical Education and Sports of the University of Sa˜o Paulo. All participants received a verbal explanation about the risks involved in their participation and signed a written informed consent form. One hundred and fifty healthy male individuals were invited to participate in this study. All participants were non-smokers, free of neuromuscular and cardiovascular dysfunctions and were not taking any medication at the time of data collection. Each individual was measured for height, body mass and body fat (Brozek et al., 1963). Additionally, participants were required to fill out an International Physical Activity Questionnaire (IPAQ-short version) to determine their physical activity levels. A moderate activity level (from 600–2999 Met-min/week) was a criterion for inclusion in this study (Fogelholm et al., 2006). Table 1 shows the anthropometric characteristics, age and IPAQ scores of the participants. The subjects performed a maximal incremental test on a motor-driven treadmill (model TK35, CEFISE, Nova Odessa, SP, Brazil). After a 3-min warm-up at 8 km/h, the treadmill speed was increased by 1 km/h every minute until exhaustion. The treadmill grade was maintained at a constant incline of 1%. The volunteers were provided with strong encouragement to continue the exercise as long as possible. Gas exchanges were measured breath-by-breath using a gas analyser (Cortex Metalyzer 3B, Cortex Biophysik, Leipzig, Germany) and were subsequently averaged over 30-s intervals throughout the test. Before each test, the gas analyser was calibrated according to the manufacturer’s recommendations. Maximal heart rate (HRMAX) was defined as the highest value obtained at the end of the test. VT (aerobic threshold) was determined _ VO _ 2 at the point of a non-linear increase in the VE/ relationship. RCP (anaerobic threshold) was determined at _ 2, a _ VCO the point of a concomitant non-linear increase in VE/ _ _ constant increase in the VE/VO2 relationship and the first decrease in the expiratory fraction of CO2 (Meyer et al., 2005). Two independent investigators, who were blinded to participant identification and genotype data, determined these thresholds. They were not co-authors of the present study. When the investigators disagreed, a third independent investigator was consulted. A third investigator determined the VT and RCP in less than 10% of the tests. Maximal oxygen _ 2 max) was determined when two or more of the uptake (VO Table 1. Anthropometric characteristics of the participants (n ¼ 150). Characteristics of the participants

Mean ± SD

Age (years) Body mass (kg) Height (cm) Body fat (%) IPAQ (score)

25.2 ± 4.0 77.8 ± 13.9 174 ± 21 13.3 ± 4.2 1309 ± 291

Values are means ± SD. IPAQ, International Questionnaire.



ACTN3 polymorphism and cost of locomotion

DOI: 10.3109/03014460.2015.1050065

following criteria were met: an increase in oxygen uptake of less than 2.1 ml/kg/min between two consecutive stages, a respiratory exchange ratio greater than 1.1 and the attainment of a heart rate 90% of the predicted maximal heart rate (i.e. 220-age) (Howley et al., 1995). CoL was measured at two different running speeds (10 and 12 km/h) during 10 minutes each on the same treadmill used for the incremental test. Both the oxygen consumed and carbon dioxide produced were measured breath by breath. _ 2 over the final 30 seconds was taken as the steadyThe VO _ 2 for a given speed and then the values were state VO converted to kcal/kg/km according to equation (1), as proposed by Fletcher et al. (2009).

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Cost of locomotionðkcal=kg=kmÞ _ 2  caloric equivalent=s=BM  K ¼ VO


_ 2 is measured in litres per minute, caloric equivawhere VO lent is in kilocalories per litre, speed (s) is in metres per minute, body mass (BM) is in kilograms and K is 1000 m/Km. _ 2 (kcal/l O2) was determined The caloric equivalent of VO taking the average RER over the same 30 second interval (Lusk, 1928). For the genotyping of the subjects, cells from mouthwashes were obtained for isolation of genomic DNA. DNA quantification was performed using a spectrophotometer (NanoDrop, ND 2000, Wilmington, DE) and the concentration was adjusted to 1 mg/mL for subsequent storage in 20  C. ACTN3 (R577X) genotypes were determined by conventional 2-primer PCR assay, which resulted in the amplification of a 291-bp fragment of the ACTN3 gene that includes the polymorphic region. PCR reaction was carried out using the following primers ACTN3-F: 50 -CTGTTGCCTGTGGTAAGTGGG-30 and ACTN3-R: 50 TGGTCACAGTATGCAGGAGGG-30 . Reaction conditions were as follows: initial hold at 95  C for 5 minutes, 45 cycles of denaturation at 95  C for 30 seconds, annealing at 60  C for 30 seconds and extension at 72  C for 30 seconds and a final extension step of 7 minutes at 72  C. The amplified fragment subsequently underwent digestion by the enzyme DdeI (New England, Biolabs, Beverly, MA) following the supplier’s recommendations. The digested products were then separated in a 3% agarose gel. According to recent recommendations for replicating genotypephenotype association studies (Chanock et al., 2007), to ensure proper internal control for each batch of analysis, we used positive and negative controls from different DNA aliquots that were previously genotyped by the same method. The RFLP results were scored by three experienced and independent investigators who were blinded to participant’s data. Data normality was assessed through Kolmogorov– Smirnov test and all variables showed normal distribution. Data are expressed as means ± standard deviations. The chisquared test was used to analyse the Hardy–Weinberg equilibrium of genotype distribution. Comparisons between genotype groups for each variable were made through a oneway ANOVA. When a significant F-value was detected, Tukey’s post-hoc test was used to allocate significant differences. All the statistical analyses were conducted using the SPSS statistical package (version 16.0, Chicago, IL). The significance level was set at  ¼ 0.05 for all statistical analyses.


Results ACTN3 genotype distribution attained the Hardy–Weinberg equilibrium, as was evidenced through the chi-square test. The frequencies of the ACTN3 genotypes were 33.9% RR, 37.8% RX and 28.3% XX. The variables measured during the maximal incremental running test are presented in Table 2. No statistical differences between ACTN3 genotypes were observed for these variables (p40.05). The comparison of the respiratory exchange ratio and the percentage that 10 km/h and 12 km/h represented from RCP speed showed no significant differences across ACTN3 genotypes (p40.05), indicating that these absolute speeds represented similar relative intensities to RR, RX and XX genotypes (Table 3). The comparison of CoL between genotypes for 10 km/h and 12 km/h running speeds are presented in Figure 1. ANOVA results showed statistical differences between ACTN3 genotypes. The caloric unit cost of the RX genotype was lower compared to XX genotype at 10 km/h (p50.05) (Figure 1(a)). Additionally, the RX genotype was also significantly more economical compared to both RR and XX genotypes at 12 km/h (p50.05) (Figure 1(b)).

Discussion The cost of locomotion has been stated as an important trait in the evolution of humans. Several factors have demonstrated influence on the energy spent during human locomotion, including the interaction between environmental and genetic factors. In particular, the ACTN3 R577X polymorphism may Table 2. Variables measured during the maximal incremental running test by ACTN3 genotype (n ¼ 150).

_ 2 max (mL/kg/min) VO HRmax (bpm) PTS (km/h) VT (km/h) RCP (km/h)




46.1 ± 5.7 190 ± 8 15.7 ± 1.2 9.9 ± 1.4 13.3 ± 1.4

47.1 ± 4.6 190 ± 9 16.4 ± 1.4 10.1 ± 1.2 13.5 ± 1.2

47.6 ± 5.5 188 ± 9 15.9 ± 1.5 10.3 ± 1.3 13.8 ± 1.7

Data are means ± SD. _ 2 max, maximal oxygen uptake; HRmax, maximal heart rate; PTS, VO peak treadmill speed; VT, ventilatory threshold; RCP, respiratory compensation point.

Table 3. Respiratory exchange ratio and percentage of the respiratory compensation point of the constant speed tests by ACTN3 genotype (n ¼ 150).

RER at 10 km/h 10 km/h (%RCP) RER at 12 km/h 12 km/h (%RCP)




0.81 ± 0.05 76.3 ± 8.8 0.94 ± 0.06 91.5 ± 10.5

0.81 ± 0.08 74.4 ± 6.8 0.95 ± 0.10 89.3 ± 8.1

0.83 ± 0.10 73.5 ± 8.6 0.96 ± 0.09 88.2 ± 10.3

Data are means ± SD. RER at 10 km/h, respiratory exchange ratio at 10 km/h; 10 km/h (%RCP), percentage of the speed associated to respiratory compensation point relative to 10 km/h; RER at 12 km/h, respiratory exchange ratio at 12 km/h; 12 km/h (%RCP), percentage of the speed associated to respiratory compensation point relative to 12 km/h.


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Figure 1. Cost of locomotion for each genotype measured at 10 km/h (a) and 12 km/h (b). *Statistically lower compared to XX. yStatistically lower compared to RR.

generate distinct phenotypes, with the X allele being beneficial to aerobic metabolism and the R allele favouring muscle strength. The purpose of the current study was to investigate the influence of the ACTN3 R577X polymorphisms on the CoL. Our results showed that RX individuals were able to sustain the same running speed with lower energy expenditure, when compared with their counterparts with the two other genotypes. In the present study, it was detected that the genotype distribution attained the Hardy–Weinberg equilibrium. In accordance with Mills et al. (2001), R and X allele frequencies vary considerably among populations. Most studies have been conducted with ethnically homogenous populations, mainly Western Eurasians, in which a mean frequency of 33%, 47% and 20% for RR, RX and XX genotypes, respectively, was observed (Druzhevskaya et al., 2008; Yang et al., 2003). Different to this, Scott et al. (2010) observed frequencies of 75%, 23% and 2% for RR, RX and XX genotypes, respectively, in 311 Jamaican individuals. Scarce data are available for the Brazilian population about the frequencies of the ACTN3 genotypes, as the available studies were conducted with smaller samples compared to other studies (Eynon et al., 2009; Yang et al., 2003). Lima et al. (2011) analysed ACTN3 genotype distribution among 234 Brazilian individuals and observed 33.3%, 50.8% and 15.9% of the RR, RX and XX genotypes, respectively. Pimenta et al. (2012) observed RR, RX and XX genotypes in 40.5%, 35.1% and 24.4% of their Brazilian sample of only 37 individuals. Although it is not possible to clearly establish the ACTN3 genotype distribution in the Brazilian population, we argue that the Brazilian population may not be as ethnically homogenous as Western Eurasians for example. With this in mind, more studies are needed to make stronger comparisons and conclusions about the distribution of ACTN3 genotypes in the Brazilian population. The ability to cover long distances has been considered an important trait in human evolution (Bramble & Lieberman, 2004). From a genetic standpoint, previous studies have proposed beneficial genotypes for different capacities (e.g. endurance and strength). Genotypes are also able to considerably influence phenotypic characteristics and this occurs mainly in homozygote individuals (Bouchard, 2012). For the

ACTN3 R577X polymorphism, in particular, RR genotype seems to positively influence very short intensive tasks, while XX genotype seems to benefit long–moderate tasks (Macarthur & North, 2004). It is interesting to observe that we detected a lower CoL in ACTN3 RX individuals compared to XX individuals at 10 km/h and lower than both RR and XX individuals at 12 km/h. Importantly, an analysis of variance showed that these two speeds represent similar relative intensities for the three ACTN3 genotypes. Previous studies have demonstrated that the ACTN3X allele seems to benefit aerobic metabolism, as supported by an improved oxidative enzyme activity and a higher running capacity during a test until exhaustion (Macarthur et al., 2007). In turn, the R allele, which confers the presence of -actinin-3, has been shown to be beneficial to strength ability in both animal (Macarthur et al., 2008) and human (Druzhevskaya et al., 2008) models. It is important to note that the ability to produce force has been considered an important factor influencing CoL. Stronger individuals are able to better store and restitute elastic energy during human locomotion, providing an additional source of non-metabolic energy (Arampatzis et al., 2006). They are also able to decrease the volume of muscle tissue recruited during an active contraction, resulting in a lower energy expenditure (Arampatzis et al., 2006). Furthermore, it is possible that stronger individuals are able to utilise a lower percentage of their maximum strength during running, contributing to a reduced energy expenditure (Storen et al., 2008). All of these mechanisms might positively influence the CoL. In this respect, since CoL could be influenced by both metabolic and neuromuscular parameters (Saunders et al., 2004), it is possible that RX genotype preserves intermediate characteristics, allowing a greater equilibrium between negative and positive genotype-induced effects. This carries for a positive phenotype (i.e. RX) to be able to reduce energy expenditure for covering a given distance. It is also interesting to note that the higher differences between ACTN3 genotypes were detected at 12 km/h; an exercise intensity representing 90% of the respiratory compensation point (Table 3). This represents an exercise intensity where there is a significant increase in type II muscle fibre recruitment for physically active individuals (Gollnick et al., 1974; Hultman, 1995). This might be linked

ACTN3 polymorphism and cost of locomotion

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DOI: 10.3109/03014460.2015.1050065

to the particular expression of the -actinin-3 in type IIa and IIb muscle fibres (Mills et al., 2001). Thus, once the ACTN3 polymorphism affects the -actinin-3 expression, it is reasonable to expect that this polymorphism has a higher functional influence in exercise intensities where type II muscle fibres are predominantly recruited. Furthermore, from an evolutionary perspective, persistence hunting, a practice which shows a high efficiency and can still be observed in central Kalahari in Botswana (Liebenberg, 2006), is not performed continuously, but intermittently. This characteristic shows that there are periods of moderate and intense running during the hunting, suggesting that the lower energy consumption while running at higher intensities (such as 12 km/h in the present study) is also important for this ancient practice. It has been hypothesised that there exists an evolutionary ‘trade-off’ between strength/power and endurance phenotypic traits, so that an individual is genetically pre-disposed towards to either short, high-intensity or long, low-intensity tasks (Garland et al., 1990). However, in analysing the trade-off hypothesis, Ruiz et al. (2013) did not observe this mechanism for the ACTN3 R577X polymorphism in swimming athletes. As previously shown, CoL is a special parameter which could be influenced by neuromuscular characteristics, such as strength and power, and physiological characteristics, such as aerobic metabolism (Saunders et al., 2004). Therefore, it would be biologically logical that the RX genotype may maximise the CoL to influence both muscle function and aerobic metabolism. In fact, we observed that individuals with this genotype were more economical compared to RR and XX individuals during locomotion at 12 km/h. However, despite the fact that CoL is an important endurance trait (Weston et al., 2000), RX is not the most frequent ACTN3 genotype among individuals with high endurance capacity (i.e. endurance athletes) (Eynon et al., 2013). Thus, it is possible that this advantage could be thought of in mainly evolutive terms, for example during running at moderate intensities, mainly for locomotion and necessary daily activities, rather than in the ancient practice of persistence hunting. In other words, the ACTN3 RX genotype may have been selected to constitute a humankind survival profile. In present day sports performance, particularly running, the athletes maintain higher intensities than daily life throughout the entire competition (Billat et al., 2003). Thus, it is possible that the ability to improve the aerobic metabolism utilisation provided by the ACTN3 XX genotype (Macarthur et al., 2007) could provide a greater athletic advantage compared to a lower CoL at low running speeds provided by the ACTN3 RX genotype. In conclusion, our results demonstrate that energy expenditure during human locomotion is positively influenced by the ACTN3 RX genotype. Our results suggest that this genotype might generate an intermediate strength-to-endurance phenotype, which would be an advantage to CoL during moderateto-intense exercise. Although the XX genotype is associated with a higher capacity to tolerate long efforts, such as longdistance running (Eynon et al., 2009; Niemi & Majamaa, 2005), and the RR genotype is associated with sprint/power performance (Yang et al., 2003), the inherent characteristics provided by the heterozygous genotype (i.e. RX) seem to build a more economical profile, at least during moderate-tointense running. From the evolutionary stand-point, this


genotype could be selected as a beneficial trait, for example, for long-term, moderate-to-intense locomotion.

Acknowledgements Leonardo A. Pasqua is supported by Sa˜o Paulo Research Foundation (grant 2010/13913-6). Romulo Bertuzzi is supported by CAPES (grant 23038.000486/2011-15).

Conflict of interest The authors declare that they have no conflict of interest.

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The genetics of human running: ACTN3 polymorphism as an evolutionary tool improving the energy economy during locomotion.

Covering long distances was an important trait to human evolution and continues to be highlighted for health and athletic status. This ability is bene...
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