genetics | sports performance
Genetics and Performance: Now science is getting to the long and the short of how genes influence performance
Scientists are slowly beginning to find the genes which play a direct role in determining exercise capacity. Recently, researchers discovered - on human chromosome No. 1 - the gene which encodes MCT1, a protein which helps transport lactate into muscle cells. Variations in this gene will no doubt determine how well an athlete can improve lactate threshold - a key predictor of endurance performance - in response to strenuous physical training.
ow, scientists at the Royal Defence Medical College and the Centre for Cardiovascular Genetics in the UK have discovered that variations in the gene which encodes a protein called angiotensin-converting enzyme (ACE) can have a large impact on exercise efficiency ('The ACE Gene and Muscle Performance,' Nature, vol. 403, p. 614, 10 February 2000).
To understand how variations in the ACE gene might influence the economy with which you run, cycle, or swim, you first need to understand what angiotensin-converting enzyme actually does. The angiotensin-converting-enzyme story begins with a plasma protein called angiotensinogen, which is present in the blood of all human beings. Under certain conditions, kidney cells secrete a hormone called renin into the blood which cleaves a 10-amino-acid protein from angiotensinogen to form a compound called angiotensin I. The various physiological roles played by angiotensin I are not completely understood, but it is known that angiotensin-converting enzyme (ACE) can knock two amino acids off angiotensin I to form a compound called angiotensin II. Angiotensin II has a variety of functions, but for purposes of our discussion we can simply say that it directly increases blood pressure by constricting arteries, and it indirectly raises blood pressure and blood volume by stimulating thirst centres in the brain and directing the kidneys to conserve more minerals and water.
The British scientists knew that there were two key variations in the ACE gene (the one which codes for angiotensin-converting enzyme). One of these has an extra 287 base pairs within its DNA and is called the 'long allele'; the other is without the base pairs and is the 'short allele'. All humans have two ACE genes; roughly 50 per cent of the world's population has one copy of each variant, 25 per cent have two short genes, and 25 per cent have the two long ones. Previous studies had shown that the long allele seems to be linked with better endurance performance and a stronger response to exercise training. For example, in one piece of research individuals with two copies of the long allele gained more muscle mass and lost more body fat during 10 weeks of intensive physical training, compared with athletes with two copies of the short gene or one copy of each gene ('Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism and Response to Physical Training,' Lancet, vol. 353 (9152), pp. 541-545, February 13, 1999).
The British researchers were not sure why that was the case, but they did know that the long allele produces a version of angiotensin-converting enzyme which is 'weaker', i. e., has lower activity, compared with the short gene. To gain a better understanding of the long-gene's effects, they recruited 58 Caucasian military servicemen into their study; 35 had two copies of the long version of the gene, and 23 possessed just the short version. All 58 men underwent an 11-week programme of endurance exercise consisting of interval training on an exercise bike.
Prior to and after the training period, the researchers calculated the 'delta efficiency' of exercise for each subject. This variable is supposed to represent the efficiency with which muscles are working, and it is basically the percentage ratio of the change in work performed per minute to the change in energy expended per minute. Delta efficiency is not a bad way to measure one's economy of exercise; basically, it reflects the fact that if you can increase your rate of working per minute (i. e., your muscular power output) without a large upswing in energy expenditure, you are efficient; if your energy consumption soars when you increase your running, cycling, or swimming speed, you are inefficient. Before the training began, the delta efficiency was the same for both groups of men (about 25 per cent). However, after training delta efficiency improved by almost 9 per cent for exercisers with two copies of the long ACE gene but remained stagnant in the short-ACE group.
What was going on? Bear in mind that one of the key - but often overlooked - adaptations you make to exercise training is in the responsiveness of your blood vessels. After you have been exercising regularly for a couple of months, your blood vessels relax more easily during exercise, increasing blood flow to your muscles. This has some obvious advantages; the spiked blood flow can bring more oxygen and fuel to your muscle fibres.
At least some of this artery expansiveness is mediated by a chemical called nitric oxide which is released by cells lining your arteries (these cells help make up the 'endothelium' - the inner layer of artery walls). Nitric oxide - 'discovered' by scientists about 20 years ago and originally thought to be an intracellular 'messenger' - not only dilates arteries but also prolongs vasodilation, keeping the good stuff flowing into your muscle cells throughout your workout or race. Incidentally, nitric oxide's actions are so powerful that nitric-oxide treatments reduce pulmonary vascular resistance in people with severe chronic obstructive pulmonary disease and are also thought to be helpful in the treatment of atherosclerosis.
Train to release nitric oxide
Exercise training increases the production of nitric oxide by your endothelium, but angiotensin II seems to decrease the rate at which nitric oxide is synthesized. Thus, we have a potential mechanism underlying the long-ACE-gene's link with better endurance performance. The long gene produces angiotensin-converting enzyme with lower activity, which means that less angiotensin II will be produced. The lower angiotensin II means that more nitric oxide can be synthesized inside artery walls during exercise, leading to stronger blood flow to the muscles. In effect, the long ACE genes let endurance-trained muscles have more blood.
It's not clear yet why this effect would improve efficiency of exercise (it seems more likely to raise VO2max and lactate threshold), unless the muscle cells most responsible for efficient movement are better supplied by oxygen and fuel in individuals with the longer ACE gene - and thus can work more continuously throughout a bout of exercise. The exercise intensities utilized in the study were low (no higher than 80 Watts), so it's possible that the combination of long ACE genes plus training opened up blood flow to slow-twitch muscle cells in the exercisers' legs, allowing them to 'take over' the burden of exercise (slow-twitch cells would be more efficient than fast twitchers at low intensities of exertion). However, Dr. Hugh Montgomery, lead scientist in the study, believes that another mechanism may be at work. Montgomery thinks that the long ACE genes may have profound metabolic effects within the muscle cells, in addition to their influence on artery walls. Basically, he suggests that the long genes may improve the efficiency of fuel selection, uptake, and utilization by muscle fibres during exercise, thus enhancing economy.
The ACE of hearts
Before rushing out to your local exercise geneticist to find out if you have the long version of ACE, bear in mind this caveat, however: so far, the efficiency improvement has only been detected at very low exercise intensities; we don't know if it will hold true at competitive speeds, too.
Of course, many will wonder whether Kenyan runners have the long-ACE genes (but probably won't speculate on how the Ethiopians were able to borrow those ACEs from the Kenyans, or how the Kenyans picked up the genes from the Finns, who borrowed them from the Brits, who took the alleles from earlier Finns, who got them from Swedes, etc.). Before this kind of thinking goes too far, however, we should point out that about 25 per cent of British and American citizens have double-long ACE genes, which in the case of Americans would mean that almost three times as many Americans hold double ACEs, compared to Kenyans, even if the entire Kenyan population had only the extended genes!
It is clear that the research has implications which range beyond endurance exercise. Drugs called 'ACE inhibitors' help cardiac cells survive heart attacks and also improve survivorship in patients with heart troubles of various kinds by easing artery tightening and perhaps in part by letting nitric oxide do its thing and improving the efficiency of cardiac muscle-cell contractions. ACE inhibitors might also help increase the mechanical and metabolic efficiency of muscles in individuals who for various reasons are energy-deprived.
The ACE work is exciting stuff, uncovering not only the genetic but also the important physiological foundations of exercise excellence. In our next issue, we'll provide you with a review of what scientists actually know about the genetic underpinnings of performance.
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