The mechanisms of action for the ACE gene and its potential role in endurance performance.

Introduction

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.

Mechanism

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).

ACE

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

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).

Ethnicity

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.

Other Factors

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.

Conclusion

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.
Reference List

Ahmetov, I. I., Williams, A. G., Popov, D. V., Lyubaeva, E. V., Hakimullina, A. M., Fedotovskaya, O. N., & Rogozkin, V. A. (2009). The combined impact of metabolic gene polymorphisms on elite endurance athlete status and related phenotypes. Human Genetics, 126, 751-761.

Alvarez, R., Terrados, N., Ortolano, R., Iglesias-Cubero, G., Reguero, J. R., Batalla, A., & Coto, E. (2000). Genetic variation in the renin-angiotensin system and athletic performance. European Journal of Applied Physiology, 82, 117-120.

Amir, O., Amir, R., Yamin, C., Attias, E., Eynon, N., Sagiv, M., & Meckel, Y. (2007). The ACE deletion allele is associated with Israeli elite endurance athletes. Experimental Physiology, 92, 881-886.

Billat, L. V., & Koralsztein, J. P. (1996). Significance of the velocity at VO2max and time to exhaustion at this velocity. Sports Medicine, 22, 90-108.

Chelly, S. M., & Denis, C. (2001). Leg power and hopping stiffness: relationship with sprint running performance. Medicine and Science in Sports and Exercise, 33, 326-333.

Coetzer, P., Noakes, T. D., Sanders, B., Lambert, M. I., Bosch, A. N., Wiggins, T., & Dennis, S. C. (1993). Superior fatigue resistance of elite black South African distance runners. Journal of Applied Physiology, 75, 1822-1827.

Costill, D. L., Branam, G., Eddy, D., & Sparks, K. (1971). Determinants of marathon running success. Internationale Zeitschrift für angewandte Physiologie einschliesslich Arbeitsphysiologie, 29, 249-254.

Collins, M., Xenophontos, S. L., Cariolou, M. A., Mokone, G. G., Hudson, D. E., Anastasiades, L., & Noakes, T. D. (2004). The ACE gene and endurance performance during the South African Ironman Triathlons. Medicine and Science in Sports and Exercise, 36, 1314-1320.

Gayagay, G., Yu, B., Hambly, B., Boston, T., Hahn, A., Celermajer, D. S., & Trent, R. J. (1998). Elite endurance athletes and the ACE I allele–the role of genes in athletic performance. Human Genetics, 103, 48-50.

Hagerman, F. C., Connors, M. C., Gault, J. A., Hagerman, G. R., & Polinski, W. J. (1978). Energy expenditure during simulated rowing. Journal of Applied Physiology, 45, 87-93.

Hennes, M. M., O’Shaughnessy, I. M., Kelly, T. M., LaBelle, P., Egan, B. M., & Kissebah, A. H. (1996). Insulin-Resistant Lipolysis in Abdominally Obese Hypertensive Individuals Role of the Renin-Angiotensin System. Hypertension, 28, 120-126.

Inagami, T., Kambayashi, Y., Ichiki, T., Tsuzuki, S., Eguchi, S., & Yamakawa, T. (1999). Angiotensin receptors: molecular biology and signalling. Clinical and Experimental Pharmacology and Physiology, 26, 544-549.

Jones, A., Montgomery, H. E., & Woods, D. R. (2002). Human performance: a role for the ACE genotype. Exercise and Sport Sciences Reviews, 30, 184-190.

Joyner, M. J. (1991). Modeling: optimal marathon performance on the basis of physiological factors. Journal of Applied Physiology, 70, 683-687.

Joyner, M. J., Ruiz, J. R., & Lucia, A. (2011). The two-hour marathon: who and when?. Journal of Applied Physiology, 110, 275-277.

Kong, P. W., & De Heer, H. (2008). Anthropometric, gait and strength characteristics of Kenyan distance runners. Journal of Sports Science and Medicine, 7, 499-504.

Levine, B. D., Lane, L. D., Buckey, J. C., Friedman, D. B., & Blomqvist, C. G. (1991). Left ventricular pressure-volume and Frank-Starling relations in endurance athletes. Implications for orthostatic tolerance and exercise performance. Circulation, 84, 1016-1023.

Liu, Y., Leri, A., Li, B., Wang, X., Cheng, W., Kajstura, J., & Anversa, P. (1998). Angiotensin II stimulation in vitro induces hypertrophy of normal and postinfarcted ventricular myocytes. Circulation Research, 82, 1145-1159.

Lucia, A., Esteve-Lanao, J., Olivan, J., Gomez-Gallego, F., San Juan, A. F., Santiago, C., & Foster, C. (2006). Physiological characteristics of the best Eritrean runners-exceptional running economy. Applied Physiology, Nutrition, and Metabolism, 31, 530-540.

Lucia, A., Olivan, J., Bravo, J., Gonzalez-Freire, M., & Foster, C. (2008). The key to top-level endurance running performance: a unique example. British Journal of Sports Medicine, 42, 172-174.

McArdle, W. D., Katch, F. I., & Katch, V. L. (2010). Exercise Physiology: Nutrition, Energy, and Human Performance. Philadelphia, PA: Lippincott Williams & Wilkins.

Min, S. K., Takahashi, K., Ishigami, H., Hiranuma, K., Mizuno, M., Ishii, T., & Nakazato, K. (2009). Is there a gender difference between ACE gene and race distance?. Applied Physiology, Nutrition, and Metabolism, 34, 926-932.

Montgomery, H., Clarkson, P., Barnard, M., Bell, J., Brynes, A., Dollery, C., & Humphries, S. (1999). Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training. The Lancet, 353, 541-545.

Muniesa, C. A., González-Freire, M., Santiago, C., Lao, J. I., Buxens, A., Rubio, J. C., & Lucia, A. (2010). World-class performance in lightweight rowing: is it genetically influenced? A comparison with cyclists, runners and non-athletes. British Journal of Sports Medicine, 44, 898-901.

Myerson, S., Hemingway, H., Budget, R., Martin, J., Humphries, S., & Montgomery, H. (1999). Human angiotensin I-converting enzyme gene and endurance performance. Journal of Applied Physiology, 87, 1313-1316.

Nisoli, E., & Carruba, M. O. (2006). Nitric oxide and mitochondrial biogenesis. Journal of Cell Science, 119, 2855-2862.

Paul, M., Mehr, A. P., & Kreutz, R. (2006). Physiology of local renin-angiotensin systems. Physiological Reviews, 86, 747-803.

Pitsiladis, Y. P., Onywera, V. O., Geogiades, E., O’Connell, W., & Boit, M. K. (2004). The dominance of Kenyans in distance running. Equine and Comparative Exercise Physiology, 1, 285-291.

Puthucheary, Z., Skipworth, J. R., Rawal, J., Loosemore, M., Van Someren, K., & Montgomery, H. E. (2011). The ACE Gene and Human Performance. Sports Medicine, 41, 433-448.

Rankinen, T., Wolfarth, B., Simoneau, J. A., Maier-Lenz, D., Rauramaa, R., Rivera, M. A., & Bouchard, C. (2000). No association between the angiotensin-converting enzyme ID polymorphism and elite endurance athlete status. Journal of Applied Physiology, 88, 1571-1575.

Reisenleiter, F., Katz, N., & Gardemann, A. (1996). Control of hepatic carbohydrate metabolism and haemodynamics in perfused rat liver by arterial and portal angiotensin II. European Journal of Gastroenterology & Hepatology, 8, 279.

Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P., & Soubrier, F. (1990). An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. Journal of Clinical Investigation, 86, 1343.

Saltin, B., Larsen, H., Terrados, N., Bangsbo, J., Bak, T., Kim, C. K., & Rolf, C. J. (1995). Aerobic exercise capacity at sea level and at altitude in Kenyan boys, junior and senior runners compared with Scandinavian runners. Scandinavian Journal of Medicine & Science in Sports, 5, 209-221.

Saunders, P. U., Pyne, D. B., Telford, R. D., & Hawley, J. A. (2004). Factors affecting running economy in trained distance runners. Sports Medicine, 34, 465-485.

Scott, R. A., Moran, C., Wilson, R. H., Onywera, V., Boit, M. K., Goodwin, W. H., & Pitsiladis, Y. P. (2005). No association between angiotensin converting enzyme (ACE) gene variation and endurance athlete status in Kenyans. Comparative Biochemistry and Physiology – Part A: Molecular & Integrative Physiology, 141, 169-175.

Sonna, L. A., Sharp, M. A., Knapik, J. J., Cullivan, M., Angel, K. C., Patton, J. F., & Lilly, C. M. (2001). Angiotensin-converting enzyme genotype and physical performance during US Army basic training. Journal of Applied Physiology, 91, 1355-1363.

Tanriverdi, H., Evrengul, H., Tanriverdi, S., Turgut, S., Akdag, B., Kaftan, H. A., & Semiz, E. (2005). Improved endothelium dependent vasodilation in endurance athletes and its relation with ACE I/D polymorphism. Circulation Journal: Official Journal of the Japanese Circulation Society, 69, 1105.

Taylor, C. R., Heglund, N. C., McMahon, T. A., & Looney, T. R. (1980). Energetic cost of generating muscular force during running: a comparison of large and small animals. The Journal of Experimental Biology, 86, 9-18.

Wang, G., Mikami, E., Chiu, L. L., de Perini, A., Deason, M., Fuku, N., & Pitsiladis, Y. P. (2012). Association analysis of ACE and ACTN3 in Elite Caucasian and East Asian Swimmers. Medicine and Science in Sports and Exercise. Advance online publication. DOI: 10.1249/MSS.0b013e31827c501f

Zhang, B., Tanaka, H., Shono, N., Miura, S., Kiyonaga, A., Shindo, M., & Saku, K. (2003). The I allele of the angiotensin‐converting enzyme gene is associated with an increased percentage of slow‐twitch type I fibers in human skeletal muscle. Clinical Genetics, 63, 139-144.

Zilberman-Schapira, G., Chen, J., & Gerstein, M. (2012). On Sports and Genes. Recent Patents on DNA & Gene Sequences, 6, 180-188.

Advertisements

Tags: , , , , , , , , , , , , ,

About scotthobbsstrength

Scott Hobbs - Strength and Conditioning Coach Scott graduated from St Marys University, London (UK) in 2014 with a B.Sc (Hons.) in Strength and Conditioning Science (First Class) and has almost completed his masters degree (M.Sc) in Sports Rehabilitation. He is a Registered Strength and Conditioning Coach (RSCC) and Certified Strength and Conditioning Specialist (CSCS) through the National Strength and Conditioning Association, a Level 1 British Weightlifting Coach, a Level 1 USA Track and Field Coach, and a certified personal trainer. With over seven years experience in the strength and conditioning field (and more than ten in the fitness/health industry), Scott has worked with amateur/club level to elite national and international athletes in sports including rowing, football, rugby, powerlifting, sprint hurdling, weightlifting, lacrosse, and tennis (amongst others). Scott currently works as an assistant strength and conditioning coach at the United States Military Academy (West Point) where he works with Army Football, Men's Rugby, Men's and Women's Tennis, and Women's Basketball. He also runs the analytics program for football and basketball, which includes GPS and readiness monitoring. Prior to West Point, he gained experience in D1 athletics at the University of Pennsylvania and Lehigh University. Before leaving the U.K. he was graduate assistant lecturer at St Mary's University where he taught undergraduate students on the Strength and Conditioning Science degree program. Other previous experience includes work with athletes at DeSales University, London Irish Professional Rugby Club, St Mary's University, and London Rowing Club. In his spare time, Scott actively competes in strength-based sports, having won a national competition in the UK and won two state meets (setting a state record in New York) in powerlifting. He also enjoys outdoor and combat-based sports. Scott currently lives with his wife, Anna, in Highland Falls, NY (USA).

Leave a Reply

Please log in using one of these methods to post your comment:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Strength and Conditioning Blog

Thoughts and reflections from a coach, lecturer and student

Matt Dickens' pureHealth pureSport

Strength and Conditioning

Martin Buchheit

Strength & Conditioning Coach, Sport Scientist and Technologist

Titanium Training

Your Strongest Resource

Mike Reinold

Physical Therapy | Athletic Training | Sports Medicine | Sports Performance | Blog

%d bloggers like this: