Unique among unique. Is it genetically determined? (2008, Jul 28)

Unique among unique. Is it genetically determined? [Br J Sports Med. 2008] – PubMed Result <http://www.ncbi.nlm.nih.gov/pubmed/18662936?dopt=Abstract>

Br J Sports Med. 2008 Jul 28. [Epub ahead of print]

Unique among unique. Is it genetically determined?

Gonzalez-Freire M <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gonzalez-Freire%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Santiago C <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Santiago%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Verde Z <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Verde%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Lao JI <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lao%20JI%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Oiivan J <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Oiivan%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Gómez-Gallego F <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22G%C3%B3mez-Gallego%20F%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Lucia A <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lucia%20A%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> .

Universidad Europea de Madrid, Spain.

The cross-country World championship is one of the best models to study characteristics needed to achieve top-level endurance athletic capacity. We report the genotype combination of a recent cross-country champion (12km race) in polymorphisms of seven genes that are candidates to influence endurance phenotype traits (ACTN3, ACE, PPARGC1A, AMPD1, CKMM, GDF8 (myostatin) and HFE). His data were compared with those of eight other runners (World class but not World champions). The only athlete with the theoretically more suited genotype for attaining World-class endurance running performance was the case study subject. A favourable genetic endowment, together with exceptional environmental factors (years of altitude living and training in this case) seems to be necessary to attain the highest possible level of running endurance performance.

Keeping Pace with ACE: Are ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists Potential Doping Agents? (2008, Dec 1)

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Keeping Pace with ACE: Are ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists Potential Doping Agents? Keeping Pace with ACE: Are ACE Inhibitors and Angi…[Sports Med. 2008] – PubMed Result <http://www.ncbi.nlm.nih.gov/pubmed/19026021?dopt=Abstract>

Sports Med. 2008;38(12):1065-79. doi: 10.2165/00007256-200838120-00008.

Related Articles <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&LinkReadableName=Related%20Articles&IdsFromResult=19026021&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Links

Keeping Pace with ACE: Are ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists Potential Doping Agents?

Wang P <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Wang%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Fedoruk MN <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fedoruk%20MN%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> , Rupert JL <http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Rupert%20JL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract> .

School of Human Kinetics, University of British Columbia, Vancouver, British Columbia, Canada.

In the decade since the angiotensin-converting enzyme (ACE) gene was first proposed to be a ‘human gene for physical performance’, there have been numerous studies examining the effects of ACE genotype on physical performance phenotypes such as aerobic capacity, muscle function, trainability, and athletic status. While the results are variable and sometimes inconsistent, and corroborating phenotypic data limited, carriers of the ACE ‘insertion’ allele (the presence of an alu repeat element in intron 16 of the gene) have been reported to have higher maximum oxygen uptake (V (2max)), greater response to training, and increased muscle efficiency when compared with individuals carrying the ‘deletion’ allele (absence of the alu repeat). Furthermore, the insertion allele has been reported to be over-represented in elite athletes from a variety of populations representing a number of endurance sports. The mechanism by which the ACE insertion genotype could potentiate physical performance is unknown. The presence of the ACE insertion allele has been associated with lower ACE activity (ACE(plasma)) in number of studies, suggesting that individuals with an innate tendency to have lower ACE levels respond better to training and are at an advantage in endurance sporting events. This could be due to lower levels of angiotensin II (the vasoconstrictor converted to active form by ACE), higher levels of bradykinin (a vasodilator degraded by ACE) or some combination of the two phenotypes. Observations that individuals carrying the ACE insertion allele (and presumably lower ACE(plasma)) have an enhanced response to training or are over-represented amongst elite athletes raises the intriguing question: would individuals with artificially lowered ACE(plasma) have similar training or performance potential? As there are a number of drugs (i.e. ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers - ARBs]) that have the ability to either reduce ACE(plasma) activity or block the action of angiotensin II, the question is relevant to the study of ergogenic agents and to the efforts to rid sports of ‘doping’. This article discusses the possibility that ACE inhibitors and ARBs, by virtue of their effects on ACE or angiotensin II function, respectively, have performance-enhancing capabilities; it also reviews the data on the effects of these medications on V (2max), muscle composition and endurance capacity in patient and non-patient populations. We conclude that, while the direct evidence supporting the hypothesis that ACE-related medications are potential doping agents is not compelling, there are insufficient data on young, athletic populations to exclude the possibility, and there is ample, albeit indirect, support from genetic studies to suggest that they should be. Unfortunately, given the history of drug experimentation in athletes and the rapid appropriation of therapeutic agents into the doping arsenal, this indirect evidence, coupled with the availability of ACE-inhibiting and ACE-receptor blocking medications may be sufficiently tempting to unscrupulous competitors looking for a shortcut to the finish line.

the Genathlete study. (2007)

Endothelial nitric oxide synthase gene polymorphism and elite endurance athlete status: the Genathlete study.
via PubMed: triathletes OR triat… by Wolfarth B, Rankinen T, Mühlbauer S, Ducke M, Rauramaa R, Boulay MR, Pérusse L, Bouchard C on 12/11/07

Endothelial nitric oxide synthase gene polymorphism and elite endurance athlete status: the Genathlete study.

Scand J Med Sci Sports. 2007 Dec 7;

Authors: Wolfarth B, Rankinen T, Mühlbauer S, Ducke M, Rauramaa R, Boulay MR, Pérusse L, Bouchard C

In the Genathlete study, we examined the contribution of three polymorphisms in the endothelial nitric oxide synthase (NOS3) gene to discriminate elite endurance athletes (EEA) from sedentary controls (SC). The EEA group included a total of 316 Caucasian males with a VO(2max) >75 mL/kg. The SC group comprised 299 unrelated sedentary Caucasian males who had VO(2max) values below 50 mL/kg. The polymerase chain reaction technique was used to amplify a microsatellite (CA)(n) repeat in intron 13, a 27 bp repeat in intron 4 and a third fragment in exon 7 containing the Glu298Asp SNP. No difference was found between the EEA and SC groups for the 27 bp repeat and the Glu298Asp polymorphism. Chi-square analysis of the overall allelic distribution of the (CA)(n) repeat revealed no significant difference between the two groups (P=0.135). However, comparing carriers and non-carriers for the most common (CA)(n) repeat alleles, we found significant differences between SC and EEA, with more EEA subjects carrying the 164 bp allele (P=0.007). In summary, we found suggestive evidence that the 164 bp allele of the (CA)(n) repeat in intron 13 is associated with EEA status and may account for some of the differences between EEA and SC.

PMID: 18067521 [PubMed - as supplied by publisher]

Gene Doping: A Review

Gene Doping: A Review

of Performance-Enhancing Genetics

Gary R. Gaffney, MD, Robin Parisotto, BA

0031-3955/07/ 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.pcl.2007.04.004 pediatric.theclinics.com

Pediatr Clin N Am 54 (2007) 807–822

“Mighty Mice” Made Mightier (2007, Aug 30)

“Mighty Mice” Made Mightier
Image Gallery

Se-Jin Lee
Comparison of body and muscle size between normal mice (left) and double mutant mice lacking myostatin and overproducing follistatin (right)

Newswise — The Johns Hopkins scientist who first showed that the absence of the protein myostatin leads to oversized muscles in mice and men has now found a second protein, follistatin, whose overproduction in mice lacking myostatin doubles the muscle-building effect.

Results of the new study by Se-Jin Lee, M.D., Ph.D., appearing this Wednesday in PloS One, show that while mice that lack the gene that makes myostatin have roughly twice the amount of body muscle as normal, mice without myostatin that also overproduce follistatin have about four times as much muscle as normal mice.

Lee, a professor of molecular biology and genetics, says this added muscle increase could significantly boost research efforts to “beef up” livestock or promote muscle growth in patients with muscular dystrophy and other wasting diseases.

Specifically, Lee first discovered that follistatin was capable of blocking myostatin activity in muscle cells grown under lab conditions. When he gave it to normal mice, the rodents bulked up, just as would happen if the myostatin gene in these animals was turned off.

He then genetically engineered a mouse that both lacked myostatin and made extra follistatin. If follistatin was increasing muscle growth solely by blocking myostatin, then Lee surmised that follistatin would have no added effect in the absence of myostatin.

“To my surprise and delight, there was an additive effect,” said Lee, who notes that these muscular mice averaged a 117 percent increase in muscle fiber size and a 73 percent increase in total muscle fibers compared to normal mice.

“These findings show that the capacity for increasing muscle growth by targeting these pathways is much more extensive than we have appreciated,” adds Lee. “Now we’ll search for other players that cooperate with myostatin so we can tap the full potential for enhancing muscle growth for clinical applications.”

Lee adds that this issue is of particular significance, as most agents targeting this pathway, including one drug being currently tested in a muscular dystrophy clinical trial, have been designed to block only myostatin and not other related proteins.

The research was funded by grants from the NIH and the Muscular Dystrophy Association and by a gift from Merck Research Laboratories.

On the Web:
http://www.jhu.edu/sejinlee/
http://www.plosone.org/home.action

French scientists seek test to detect gene doping in athletes (2007, Aug 21)

South Florida Sun-Sentinel.com
UF, French scientists seek test to detect gene doping in athletes
Staff report

August 21, 2007

Gene doping has the potential to spawn athletes capable of out-running, out-jumping and out-cycling the strongest of champions. But research under way at the University of Florida could help level the playing field by detecting the first cases of gene doping in professional athletes before the practice enters the mainstream.

In the wake of recent Tour de France drug violations ˜ and with the 2008 Olympics looming ˜ the need to stay ahead of the game has never been more evident. That’s why the Montreal-based World Anti-Doping Agency, or WADA, charged with monitoring the conduct of athletes, is working with investigators around the globe to develop a test that would bust competitors for injecting themselves with genetic material capable of enhancing muscle mass or heightening endurance.

“If an athlete injects himself in the muscle with DNA, would we be able to detect that?” asked one of France’s leading gene therapy researchers, Philippe Moullier, M.D., Ph.D., an adjunct professor of microbiology and molecular genetics at UF and director of the Gene Therapy Laboratory at the Universite de Nantes in France.

Right now the answer is no, he said. But the UF scientists are among several groups collaborating with national and global anti-doping organizations to develop a test that could detect evidence of “doped” DNA.

“WADA has had a research program in place for some years now, to try to develop tests for gene-based doping,” said Theodore Friedmann, M.D., head of the agency’s panel on genetic doping and director of the gene therapy program at the University of California, San Diego.

It sounds futuristic, but experts say it’s only a matter of time. Unscrupulous athletes began showing an interest in gene doping in 2004, when the first reports of muscle-boosting therapies in mice were published by University of Pennsylvania researchers.

Since then, several potential targets of gene doping have emerged, including the gene for erythropoietin, or EPO. A bioengineered version of the hormone, currently on the market, increases red blood cell production in patients with anemia and boosts oxygen delivery to the body. In athletes, this translates to enhanced stamina and a competitive edge.

But because synthetic hormones such as EPO are prohibited by WADA and readily detected through drug tests, performance-driven athletes have begun searching for stealthier and more powerful alternatives.

“The next variation of boosting red blood cell production is to actually inject the EPO gene itself, which would cause increases in red blood cells,” said Richard Snyder, Ph.D., an assistant professor of microbiology and molecular genetics at UF and director of UF’s Center of Excellence for Regenerative Health Biotechnology. “So the idea is to develop a test that could detect the gene that’s administered.”

The task isn’t easy ˜ the researchers are faced with a myriad of uncertainties, such as which tissues in the body to sample and how to distinguish a “doped” gene from a naturally occurring form of the gene. Ultimately, the test will compare how many copies of the EPO gene are found in an athlete’s body to levels found in the average person who has not been doping.

“Our research aims to develop the ability to detect gene doping, primarily in athletes. But it has a wider purpose, and that’s to understand how gene therapies are disseminated throughout the body,” added Snyder, whose research stemmed from a cooperative agreement between the UF Genetics Institute and two biomedical research organizations in France: INSERM, the French version of the National Institutes of Health, and the French national blood bank, Etablissement Francais du Sang Pays de Loire. The agreement allows Snyder and Moullier to pool their expertise and resources.

A major objective of the UF-French collaboration is to decipher the structure of AAV, a virus commonly used to deliver genes into the body for therapeutic purposes. Gene “doping” would enter the body through a similar route, but scientists say the two procedures are as different as night and day from a therapeutic standpoint.

Copyright © 2007, South Florida Sun-Sentinel <http://www.sun-sentinel.com/>

Marathon Mice and PPARd

Press release from The Salk Institute. It is intriguing that any connection is made between this work and athletic performance. Clearly, the scientist’s work is aimed at medical intervention and yet the prospects for athletes are implied through the communication. It is a further indication of how the application of pharmaceuticals to sports is sexy enough to spice up scientific research, but that most scientists are not really alarmed by how their work might be used for non-therapeutic purposes. Equally, perhaps Dr Evans is working with WADA to ensure they have tests for any future product that might arrive on the market. While I don’t think that this would be enough to deal with the use of dangerous substances in sport, it would be an important development.

Altering steroid receptor genes creates fat burning muscles, resistance to weight gain, and lowered inflammation.

April 04, 2005 La Jalla, CA — The Salk Institute scientist who earlier discovered that enhancing the function of a single protein produced a mouse with an innate resistance to weight gain and the ability to run a mile without stopping, has found new evidence that this protein and a related protein play central roles in the body’s complex journey to obesity and offer a new and specific metabolic approach to the treatment of obesity related disease such as Syndrome X (insulin resistance, hyperlipidemia and atherosclerosis).

Dr. Ronald M. Evans, a Howard Hughes Medical Investigator at Salk Institute’s Gene Expression Laboratory, presented two new studies Monday, April 4, at Experimental Biology 2005 in the scientific sessions of the American Society for Biochemistry and Molecular Biology.

The studies focus on genes for two of the nuclear hormone receptors that control broad aspects of body physiology, including serving as molecular sensors for numerous fat soluble hormones, Vitamins A and D, and dietary lipids.

The first study focuses on the gene for PPARd, a master regulator that controls the ability of cells to burn fat. When the “delta switch” is turned on in adipose tissue, local metabolism is activated resulting in increased calorie burning. Increasing PPARd activity in muscle produces the “marathon mouse,” characterized by super-ability for long distance running.

Marathon mice contain altered muscle composition, which doubles its physical endurance, enabling it to run an hour longer than a normal mouse. Marathon mice contain increased levels of slow twitch (type I) muscle fiber, which confers innate resistance to weight gain, even in the absence of exercise.

Additional work to be reported at Experimental Biology looks at another characteristic of PPARd: its role as a major regulator of inflammation. Coronary artery lesions or atherosclerosis are thought to be sites of inflammation.

Dr. Evans found that activation of PPARd suppresses the inflammatory response in the artery, dramatically slowing down lesion progression. Combining the results of this new study with the original “marathon mouse” findings suggests that PPARd drugs could be effective in controlling atherosclerosis by limiting inflammation and at the same time promoting improved physical performance.

Dr. Evans says he is very excited about the therapeutic possibilities related to activation of the PPARd gene. He believes athletes, especially marathon runners, naturally change their muscle fibers in the same way as seen in the genetically engineered mice, increasing levels of fat-burning muscle fibers and thus building a type of metabolic ’shield” that keeps them from gaining weight even when they are not exercising.

But athletes do it through long periods of intensive training, an approach unavailable to patients whose weight or medical problems prevent them from exercise. Dr. Evans believes activating the PPARd pathway with drugs (one such experimental drug already is in development to treat people with lipid metabolism) or genetic engineering would help enhance muscle strength, combat obesity, and protect against diabetes in these patients.

Link to site

Genetic tests for Rugby team

Dennis, C. (2005). “Rugby team converts to give gene tests a try.” Nature 34: 260.

Carina Dennis writes in Nature about an Australian rugby league team which aims to use genetic tests to stream-line training methods. The article quotes someone from the Australian Law Reforms Commission, whose report ‘Essentially Yours’ deals with this subject at some length. Australia seems to be taking a leading role in thinking through these issues. Ron Trent’s work at the University of Sydney is central to this research and he claims that we still do not know enough about genes for this purpose. Issues of privacy and discrimination are central to this topic. Will genetically risky athletes be prevented from participation? Will young children who dont fit the profile be excluded? Will sports authorities have the legal power to demand genetic info from athletes?

HFL to lead gene doping research

Quote from UK Sport link

“The World Anti-Doping Agency (WADA) has announced a major research award of $400,000 (£212,000) to HFL – one of the UK’s WADA-accredited laboratories. The funding will support a three-year programme managed by HFL which aims to develop suitable detection methods for gene doping.

WADA defines gene doping as “the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance”. The practice is banned under the WADA list of prohibited substances or methods, although there is currently no way in which it can be detected.

With the support of WADA funding, HFL will manage a consortium of scientific experts on gene doping from Nottingham Trent University and the Royal Free Hospital in London. “As soon as new technology becomes available, it is subject to abuse by those who have no interest in fair competition,” said David Hall, Chief Executive Officer of HFL. “This funding will help us to develop methods of detecting gene manipulation.”

The potential threat of gene doping has been long recognised by WADA, which has devoted a significant share of its research funds finding a solution to the problem. This concentrated effort is back by John Scott, Director of Drug-Free Sport at UK Sport. “Gene therapy is a major medical breakthrough which could transform the lives of many people who suffer from muscle wasting diseases,” he said. “However, it is also a dream come true for an athlete wishing to cheat, particularly while it remains undetectable.

“The development of such a detection method is key in protecting the integrity of sport, and it is testimony to the expertise at our disposal that British scientists are at the forefront on this research.”

In addition, HFL has been awarded up to £800,000 by the Horserace Betting Levy Board (HBLB) to investigate gene doping specifically for the horseracing industry”

It is great that the UK is moving on this. I met Ian Gibson MP in July 2004 to discuss the state of anti-doping in the UK. He agreed that this issue needs to be placed on the political agenda. This is one indication that some wheels are turning but where’s the ethical framework for the strategy? Detect-test is only part of the system.

Gene Doping May Not Elude Testing

Quoting from WebMD:

“In a letter published in the August issue of Molecular Therapy, French researchers say they found good reason to believe gene doping may be detectable.

In their study, monkeys were genetically doped with erythropoieten (EPO), a hormone that stimulates red blood cell formation and is often used to increase endurance in sports. Treatment with the hormone currently requires repeated injections and is detectable by antidoping urine tests.

But in this case, the EPO gene was injected directly into the monkey’s muscle tissue. Researchers say muscle is a likely target for gene dopers, because it’s easily accessible and plentiful.

Contrary to what had been predicted, the results of the experiment showed that the EPO protein produced by the genetically doped monkeys was different than the EPO protein produced naturally by nonenhanced animals and the injected gene produced was detectable by DNA screening. They say further tests are needed to determine if EPO gene doping would be detectable in urine tests.

“Although other methods of gene transfer exist and may be exploited for gene doping, and such methods are yet to be investigated, our results provide encouraging evidence that doping by gene transfer will likely not go undetected at least when skeletal muscle is the target,” write researcher Françoise Lasne of thetNational Anti-Doping Laboratory in Chatenay-Malabry, France, and colleagues.”

SOURCES: Lasne, F. Molecular Therapy, August 2004; vol 10. News release, American Society of Gene Therapy.