Running Science

by Owen Anderson

  The changes observed in O2max, lactate production, ammonia production, and running economy in response to training in these Kenyan runners appear to be routine: Nothing extraordinary stands out. However, to truly compare trainability between Kenyan and non-Kenyan runners, a study needs to involve non-Kenyans of a similar age and fitness level. Such a study does exist: Several years ago, French researchers asked a group of 16- and 17-year-old Caucasian men to participate in an endurance-training program very similar to the Nandis’ training regime.12 Training duration was 3 months for the Caucasians and 12 weeks for the Kalenjins, workout frequency was four sessions per week for both groups, and training intensity focused on 80 to 90 percent of maximal heart rate for both groups.

  After their 3-month program, the Caucasians improved O2max by 11.6 percent, a gain similar in magnitude to the 10.2 percent uptick enjoyed by the Nandi town runners and larger than the 5.4 percent increase achieved by the Kenyan villagers. There is no worry that the Caucasians’ initial fitness was low, thus leading to an unusually large expansion of maximal aerobic capacity. In fact, the Caucasians began their training with average O2max values of 58.4 ml kg-1 min-1, very similar to the pretraining level of the Nandi village runners. In effect, the Caucasians’ gain was twice as great as the Nandis’ when initial aerobic capacities were similar. In other areas of fitness, the training-related changes in heart rate, blood lactate, and plasma ammonia observed in the Nandi runners were very similar to the changes observed in Caucasians.

  This research suggests that Kenyans do not enjoy greater trainability when compared with Caucasians of similar age and initial fitness. There is also no evidence that Kenyans have higher frequencies of the highly touted I allele performance gene. Even if they did, approximately 25 percent of U.S. citizens, or about 75 million people, have two I alleles. This is nearly three times the entire population of Kenya. So, even if all Kenyans had two copies of the I allele, the United States would still have a genetic edge in terms of the total numbers of individuals with heightened delta efficiency.

  Other Genes Affecting Running Performance

  Another gene that has an effect on running performance codes for insulin-like growth factor I (IGF-I), a protein that stimulates muscle growth and repair. This coding (or creation) is indirect, involving chemical intermediates, such as transfer RNA (tRNA) and messenger RNA (mRNA). To date, the IGF-I research has been carried out only with rodents, but it is reasonable to assume that the results could apply to human runners. In 1998 H. Lee Sweeney and his colleagues at the University of Pennsylvania, working together with Nadia Rosenthal and her co-workers at Harvard University, infected mice with adeno-associated viruses (AAVs), which carried the gene coding for IGF-I.13 When these AAVs were injected into young mice, their muscular growth rates became 15 to 30 percent greater than normal; as the mice matured, their muscles became super-sized even though the animals were totally sedentary. When the AAVs were injected into middle-aged mice, their muscles resisted the expected losses in strength and function as the mice grew older.

  In follow-up work, Sweeney’s group and a team led by Roger P. Farrar of the University of Texas at Austin injected AAVs carrying the gene coding for IGF-I into one leg of each laboratory rat and then made the rodents complete an 8-week program of strength training.14 The rats carried out their training several times a week, climbing up wire ladders with weights attached to their bodies. After 8 weeks, the muscles treated with the AAV were roughly twice as strong as the muscles in the noninfected legs in the same animal. When training stopped, the muscles treated with AAV lost their strength much more slowly compared with muscles in the other legs that had engaged in strength training but had not benefited from the gene-laced viral infection.

  Other genes are likely to play a role in determining running performance. Eero Mantyranta, a Finnish cross-country skier who won two world championships plus seven medals over the course of four different Olympic games, had a genetic condition called primary familial and congenital polycythemia (PFCP) caused by a mutation in the erythropoietin receptor (EPOR) gene. This condition produces dramatic increases in blood hemoglobin, red blood cell mass, and the oxygen-carrying capacity of the blood, which are potentially great advantages in endurance sports. Many of Mantyranta’s relatives who carry the same mutated gene have also been champion Finnish endurance athletes.15

  Australian researchers have discovered a gene known as ACTN3 that seems to play an important role in optimizing the function of fast-twitch muscle fibers. An unusually high percentage of elite sprinters have a copy of this gene, and top-level female sprinters tend to have two copies of ACTN3.16

  Gene Doping

  Serious athletes, coaches, and managers are becoming increasingly aware that so-called super-performance genes exist, and some are beginning to look into the possibility of gene doping: having desirable genes added to individuals’ genetic constitutions. The technology for doing so is available. While there are different ways to supplement a human’s natural DNA constitution with outside genetic material, viruses have become a favored transporter mechanism for coveted genes because they are so adept at eluding the defenses put up by an individual’s immune system.

  The way in which gene doping is accomplished is straightforward. First, researchers select a type of virus that has a low probability of producing a serious infection. The researchers then strip down the viruses’ genetic material, leaving only the genes that code for the viruses’ outer coats, the protein wrappers that surround the inner core of genetic material. To these coat genes researchers add the genetic material of interest, for example the gene coding for IGF-I. The resulting, highly unusual viruses can then be injected into muscle tissue where they enter muscle cells and may insert the added gene into the muscle fibers’ genetic packages within the cell nuclei. The muscles may then go on an IGF-I production spree, and muscular growth can be dramatically enhanced.

  IGF-I

  The gene for IGF-I is perhaps one of the most likely to be used for doping. If the chemical IGF-I were injected by itself, instead of the gene for IGF-I, it would be broken down easily by various processes and would have little effect on muscle growth.17 However, the gene for IGF-I can be easily vectored into human muscles, via the viral mechanism mentioned earlier, where it can create a massive overproduction of IGF-I. Once the IGF-I genes take up shop within muscle cells, the results can be dramatic. IGF-I’s key action appears to be on satellite cells, essentially muscle stem cells that normally reside between muscle fibers in an intact muscle. When the stem cells are hit with concentrations of IGF-I that are higher than normal, they undergo a flurry of activity, dividing and eventually fusing with muscle cells to create stronger, larger fibers capable of greater force production. As a result, IGF-I’s actions might improve maximal running speed in endurance runners. However, it is important to note that IGF-I stimulates tumors as well as satellite cells to increase their activity.

  Myostatin

  A key physiological process always has a counterpoint mechanism to keep it from going out of control. While IGF-I stimulates satellite-cell activity and muscle growth and repair, these same activities are dampened by the action of a chemical called myostatin. It is the interplay between IGF-I and myostatin that ultimately creates a runner’s characteristic physique. If a runner undertakes vigorous strength training with heavy weights, for example, IGF-I production is amplified and myostatin creation is toned down producing muscle enlargement, or hypertrophy. If a runner sits in a rocket ship on a long ride to the moon, on the other hand, myostatin will take over, leaving him or her with wasted, weaker muscles by the end of the journey.

  Myostatin control is another potential avenue for gene doping by using either a gene that creates a protein product that blocks normal myostatin action or—perhaps better yet—a gene that creates a nonfunctional form of myostatin. Pharmaceutical and biotech companies are already working on various forms of myostatin inhibitors, stimulated by work previously carried out in the cattle industry.
Certain cattle, notably the Belgian Blue and Piedmontese breeds, have a genetic variation that creates an ineffective form of myostatin. The result is not a defective cow but rather a ripped, astonishingly muscle-bound specimen. The so-called good news for athletes interested in gene doping is that the absence of normal myostatin in these cattle also obstructs the creation of fatty tissue, which in the end gives the animals incredible body compositions. The same effects would likely occur in human runners, although the risks are unknown.

  EPO

  While endurance athletes might not necessarily be interested in IGF-I promoters or myostatin blockers because of worries about excessive muscle growth, some will certainly be attracted to the gene that stimulates increased production of erythropoietin (EPO), the compound that boosts red blood cell production by the bone marrow. A synthetic form of EPO, a drug called Epoietin that was originally developed to treat anemia, has been widely used by Tour de France cyclists in order to expand O2max and thus endurance. An entire team of cyclists has been excluded from the famous race because of EPO use, but its use in sports continues.17

  The gene for EPO is readily available, and science has already looked at what happens to monkeys, baboons, and macaques when they are supplied with the gene. The results have been predictable: Macaques, for example, dramatically increase their red blood cell production when they are given the EPO gene. However, the resulting physiological processes make many observers believe that gene doping with EPO material is much like opening a pernicious Pandora’s box. The macaques that received the EPO genes, for example, produced so many red blood cells that their blood became like sludge, increasing the risk of heart failure. As a result, macaques with EPO genes must have blood removed on a regular basis to reduce the risks of clotting and heart failure.18

  Paradoxically, some of the macaques with EPO genes eventually developed severe anemia. As it turned out, the excess EPO created by the macaques was slightly different from their normal version of EPO, perhaps because it was being created in unusual locations in the macaques’ bodies, not just in its usual production site in the kidneys. As a result, the animals’ immune systems began clearing the excess EPO and in the process also attacked normal EPO, leading to a massive falloff in EPO levels and thus a plummeting rate of red blood cell creation. This kind of immune system overreaction is a key danger associated with gene therapy and gene doping.

  PPAR-Delta

  Based on initial studies with rodents, there are a number of genes in addition to ACTN3 and the genes for IGF-I and EPO activity that could have major upsides for athletes. Researchers at the Salk Institute in San Diego, California, have inserted genes that code for a fat-burning protein called PPAR-delta into mice. The idea was to help prevent obesity in these mice, which did stay slender even when ingesting a high-fat diet. An extremely interesting aspect of this research, however, was that the mice also developed an extraordinarily large number of slow-twitch muscle cells, the kinds of fibers that are so valuable for extended endurance performance. As Ronald Evans, one of the Salk investigators put it, “This change produced the ‘marathon mouse,’ able to run twice the distance of its normal littermates.”19

  AMPK

  Scientists at Dartmouth college have worked with mice bearing a gene that codes for a highly activated form of an enzyme called AMP-activated protein kinase (AMPK).20 The activities and functions of this enzyme are complex, but one of its key effects appears to be the activation of glycogen synthase, the enzyme that boosts glycogen storage within muscles. As a result, mice carrying the special gene for activated AMPK have unusually large glycogen depots in their leg muscles and can exercise for unusually long periods of time. “Our genetically altered mouse appears to have already been on an exercise program,” notes Dr. Lee Witters, a professor of medicine and biochemistry at Dartmouth Medical School.21

  Conclusion

  An important point for runners and coaches to understand is that while specific genes seem to promote higher performance, having such genes is not mandatory in order for runners to improve dramatically or even achieve elite status as long-distance competitors. If we examined the 20 fastest 10K runners from Kenya or Ethiopia, for example, not all would have two copies of the I allele for the ACE gene; in fact, their ACE-allele frequency would be no different from the frequency observed in the general population.22 Currently no reason exists for any runner to think he or she lacks the genetic credentials to achieve dramatic improvement in performance.

  In addition, although gene doping may seem to be an attractive option for runners focused on achieving unusually large gains in performance, the practice is neither predictable nor safe. Unusual—and sometimes lethal—side effects can occur when a runner’s natural genetic makeup is artificially manipulated.

  Chapter 3

  Genetic Differences Between Elite and Nonelite Runners

  Specific genes can have a positive impact on running ability (as described in chapter 2), and thus geneticists and exercise scientists have wondered whether top-level runners have an optimal genetic profile, that is, the right combination of performance-related genes. The fundamental questions include the following: Is the DNA of an elite runner quite different from the genetic material of those who perform in the middle of the pack? Is a certain DNA dossier required to achieve elite running status? Do elite runners who climb to the highest level of endurance performance—the world champions and Olympic medalists—have unique genes that other elites lack?

  Research Examining Genetic Differences

  Researchers from the Karolinska Institutet in Stockholm, Sweden, investigated these possibilities by comparing the genetic makeup of 46 elite Spanish Caucasian athletes with the genetic composition of 123 Spanish Caucasian sedentary control individuals.1 The Karolinska investigators examined the frequency of seven genes known to have an effect on endurance performance and computed what they called a “genotype score” for each individual based on the presence or absence of the seven favorable genes, with 100 being the maximal possible rating.

  The 46 elites had an average score of 70.2, significantly higher than the 62.4 mark for the controls, implying that top athletes have superior genetic profiles. However, not a single elite athlete had the best possible score for the seven genes, and only 3 of the 46 top performers had the right makeup for six of the performance genes. Such findings suggest that it is not necessary to have all the best genes to be an elite athlete. Expressed another way, elite athletes may be slightly different genetically from nonelites, but having a superb genetic makeup is not mandatory in order to become a top-level athlete.

  Along similar lines, investigations carried out with elite Polish rowers have revealed that these high-level performers have a higher frequency of the I allele of the angiotensin-converting enzyme (ACE) gene (see chapter 2) by a margin of 56 to 44 percent.2 Such a finding suggests that the I allele is an important ticket for admission to the elite-athlete club, yet almost 20 percent of the elite Polish rowers carried no I allele at all in the ACE position, while another 51 percent had just one copy of the I allele instead of the possible two copies.

  Other studies have found a higher frequency of ACTN3, another performance-related gene, in elite endurance athletes in Finland3 and also in power athletes (sprinters and throwers) in Greece.4 In the latter study, 48 percent of elite power-oriented athletes in Greece had the RR genotype for the ACTN3 gene (the R allele of the ACTN gene is linked with greater muscle size and power), compared with just 26 percent of the overall nonelite population in Greece, a significant difference. This finding suggests that elite, power (sprint) athletes are indeed genetically different from nonelite athletes and sedentary control individuals. However, the data also reveal that having a certain genotype is not necessary to become an elite athlete: In the study from Greece, 52 percent of the power athletes did not have the RR genotype, and yet were elite. Individuals without the optimal genetic makeup can still become elite.

  In addition, some research has failed to find any conne
ction at all between the ACTN3 genotype and athletic status. In an inquiry carried out with Caucasian individuals of European ancestry, 50 top-level male professional cyclists and 52 Olympic-class male professional runners were found to have essentially the same ACTN3 compositions as 123 healthy but sedentary control subjects.5

  Numerous studies have failed to find any genetic discrepancy at all between elite and nonelite athletes. In one investigation, scientists from Israel, Portugal, Spain, and Sweden compared the frequency of the T allele of the GNB3 C825T gene, believed to have a positive impact on maximal aerobic capacity, in 174 elite endurance athletes and 340 nonathletic control individuals.6 In this research, which included participants from two different ethnic and geographic backgrounds (Israel and Spain), the likelihood of having the key T allele was no greater in elites than in controls.