The mechanisms of action for the ACE gene and its potential role in endurance performance.
Many genetic elements have been discovered that affect human physical performance (Zilberman-Schapira, Chen, & Gerstein, 2012), among these, the polymorphisms of the angiotensin I-converting enzyme (ACE) gene have undergone scrutiny. Rigat et al. (1990) discovered two polymorphic alleles of the ACE gene that correlate with concentration of ACEplasma, an insertion allele and a deletion allele. Insertion/deletion (I/D), double insertion (I/I), and double deletion (D/D) alleles all exist within the population (Jones, Montgomery, & Woods, 2002). Research has attempted to find correlations between ACE polymorphism and sporting performance with the goal of qualifying the use of ACE gene concentration as a performance biomarker; however confounding factors such as economy, ethnicity, sporting discipline and other gene interactions are present. A high level of endurance performance (EP) refers to success in an exercise that relies on, amongst other things, an individual’s maximum aerobic capacity (VO2Max), this being the maximum amount of oxygen which can be inhaled, absorbed into the vascular system, transported, and used by the working muscles (McArdle, Katch, & Katch, 2010). This paper looks at the potential role of the ACE gene on EP.
ACE affects the renin-angiotensin system (RAS) (Figure 1), an endocrine system present in blood plasma and local tissues including the heart, vasculature, and kidneys. Research deduces it to be responsible for regulation of blood pressure, fluid homeostasis maintenance, regulation of tissue growth and response to trauma (Paul, Mehr, & Kreutz, 2006). Beginning in the RAS, angiotensinogen, a liver produced serum globulin, is cleaved by renin, a peptide hormone secreted renally due to sympathetic activity or hypotension. This mechanism creates angiotensin I (ANG I), a peptide precursor to angiotensin II (ANG II) (Puthucheary et al., 2011). ACE, secreted predominantly by pulmonary and renal endothelial cells, although also present in circulation as ACEplasma, converts ANG I to ANG II (Montgomery et al., 1999). ANG II has an agonistic effect on the angiotensin type 1 receptor (AT1R), which is responsible for its substantial cardiovascular effects. AT1R activation increases arterial blood pressure due to arterial vasoconstriction and water retention through the release of aldosterone, a steroid hormone produced by the adrenal cortex. It additionally stimulates sympathetic nervous system (SNS) activity, further increasing vasoconstriction and elevating heart rate (Inagami et al., 1999) and is linked to left ventricle hypertrophy (Liu et al., 1998). ACE has an additional effect on the vasodilator peptide bradykinin, whereby it is inhibited and diminishes hypotensive ability (Tanriverdi et al., 2005).
Studies have found correlations between the ACE gene and EP, especially in athletes with a greater concentration of the I-allele (Myerson et al., 1999; Gayagay et al., 1998). The I-allele is linked to improved cardiovascular function and therefore oxygen delivery to working muscles (Hennes et al., 1996; Jones, Montgomery, & Woods, 2002), which can be quantified through measurement of VO2Max using Fick’s equation (McArdle, Katch, & Katch, 2010). The I-allele increases stroke volume, a limiting factor in cardiac output and thus VO2Max, via an increase in preload due to vasodilation and the Frank-Starling mechanism (Levine, Lane, Buckey, Friedman, & Blomqvist. (1991). Vasodilation also affects arteriovenous oxygen (a-vO2) difference, which also influences VO2Max. Hagberg, Ferrell, McCole, Willund & Moore (1998) found subjects with the I-allele had a large a-vO2 difference, possibly due to greater release of vascular tone (due to vasodilation) and therefore increases in capillary perfusion. This could also be due to the I-allele’s link to an increased percentage of type I muscle fibres which had a greater capillary density than type II, leading to increased blood supply and oxygen diffusion (Zhang et al., 2003). Additionally nitric oxide release due to bradykinin activity, along with its vasodilation effect (Tanriverdi et al., 2005), may stimulate mitochondrial biogenesis (Nisoli & Carruba, 2006) leading to higher mitochondrial density and hence energy production. Evidence, however, suggests EP success is not just a product of physiological factors, with studies showing variable performance in athletes with the same VO2Max (Joyner, 1991; Lucia et al., 2008).
Economy is defined as the energy demand for a given velocity of submaximal exercise (Saunders, Pyne, Telford, & Hawley, 2004) and is improved by minimising superfluous factors; studies (Coetzer et al., 1993; Lucia et al., 2008) have shown its elements to be better predictors of EP than VO2Max. A multitude of elements can influence success in athletes with identical VO2Max and have been proposed as key in running economy. These include biomechanical and biochemical factors, which will indirectly relate to oxygen kinetics and may result in more efficient substrate utilisation and decreased metabolic heat production and thus reduced thermal stress. Fractional utilisation is the greatest percentage of VO2Max an athlete can sustain for the duration of a race and is a key determinant of EP (Costill, Branam, Eddy, & Sparks, 1971). Another determinant is velocity at VO2Max (vVO2Max), this is the speed which an athlete can maintain whilst at 100% of their VO2Max and is crucial to success in a competitive environment (Billat & Koralsztein, 1996).
It has also been shown that highly economical runners have short ground contact times (GCT) resulting in less braking/decelerating forces and greater vertical displacement (Kong & De Heer, 2008). GCT can be affected by anthropometrics (Lucia et al., 2006) and stiffness (Chelly & Denis, 2001), an athlete with good energy storage capacity and low compliance in tendons, and optimal foot and ankle structure will have decreased GCTs. Body mass also plays a part, and when adjusted for essential weight of organs and muscle, is made up of considerable deadweight including bone, connective tissue, and fat mass. When deadweight is excessive, there is an increase in propulsive and support forces, decreasing energy efficiency as more muscle mass is activated (Taylor, Heglund, McMahon, & Looney, 1980).
East African runners hold the most records for EP of any population (Joyner, Ruiz, & Lucia, 2010). Naturally there has been speculation as to the factors underlying the success of these athletes in comparison to other populations, one being the association between ACE genotype and ethnicity. Studies have shown that ACE genotype and its relationship to endurance success varies, with most studies suggesting a positive association between the I-allele and Caucasian endurance athletes (Rigat et al., 1990; Collins et al., 2004), but a negative association with black African endurance athletes (Scott et al., 2005). It seems that in homogenous groups of ethnicity, sporting level and sporting discipline there is a relationship (Wang et al., 2012). Collins’ et al. (2004) study on South African ironmen found a higher frequency of the I-allele in the fastest 100 South African-born finishers, an outcome witnessed in studies by Alvarez et al. (2000) and Myerson et al. (1999). Research on heterogeneous cohorts by Sonna et al., (2001) and Rankinen et al. (2000) have failed to find a positive correlation between the I-allele and EP. Rankinen investigated ACE genotype in elite Caucasian endurance athletes finding no association, potentially due to the diverse mixture of sports included, which have extensive physiological demands. A divergent finding by Amir et al. (2007) was the positive relationship between the D-allele and EP in Caucasian Israeli athletes, prompting more questions about the ACE genotype’s effect in different populations.
Perhaps the Kenyan endurance success is not related to ACE genotype, Saltin et al. (1995) and Lucia et al. (2006) compared performance in African and Caucasian runners, finding, although equal in VO2Max score, fractional utilisation and vVO2Max was superior in the Africans. Additionally Africans were shown to have a lower body mass index, body fat percentage and a higher hamstring to quadriceps ratio (Kong & De Heer, 2008). Pitsiladis, Onywera, Geogiades, O’Connell, & Boit (2004) suggested that physiological adaptations to living at altitude, African ‘running’ culture and diet could be explanations of their impressive economy and endurance success.
It can also be established that there are other components that influence ACE genotype. According to Wang et al. (2012) variations in I-allele occur depending on the sporting discipline investigated. The majority of studies that have found a positive link between the I-allele and performance have been on cyclical sports, predominantly running, cycling, mountaineering and swimming (Puthucheary et al., 2011). Conversely Muniesa et al. (2010) found the I-allele was less common in rowing which, although an endurance sport, has a prominent power emphasis. Research has been carried out on other genes that are correlated to EP since two thirds of variance in athlete status is said to be affected by genetics (Ahmetov et al., 2009). Ahmetov et al. (2009) analysed 1423 athletes of various sports and found three genetic markers specifically associated with EP, NFATC4, TFAM and PPARGC1B. The former two alleles code for transcription factors which initiate cellular processes, whereas the latter allele is a co-activator of a transcription factor, they are all linked to mitochondrial biogenesis, substrate metabolism and cardiac hypertrophy. This finding suggests that elite EP likely depends on an individual’s endurance-related genetic make-up.
The ACE gene is just one factor that ties into successful EP, with its I-allele linked to improved cardiovascular function and muscular efficiency and the D-allele with sprint/power performance, however the mechanisms are inadequately explored. The majority of studies find an association between the I-allele and EP; however it seems to be an inconsistent relationship that presents itself only in homogenous cohorts of similar sporting discipline and competitive level. This is potentially due to interpretation of the results found and the fact that correlation does not imply causation. Other factors have been presented as significant performance predictors, economy being of high importance and reportedly a better predictor of endurance success than VO2Max, and ethnicity being influential through numerous facets to endurance success – as proven by distance running records. To summarise, successful EP is dependent on many factors, with the effects of ACE only significant in certain situations and populations, and even then its effects are minor and further research is needed into other genes that work with ACE in linkage disequilibrium or affect performance individually.
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