Insights into how muscle adapts to endurance

Duke University Medical Center researchers have identified the skeletal muscle changes that occur in response to endurance exercise and have better defined the role of vascular endothelial growth factor (VEGF) in creating new blood vessels, known as angiogenesis, in the process.

VEGF is a protein known to trigger blood vessel growth by activating numerous genes involved in angiogenesis.

The researchers’ new insights could provide a roadmap for medical investigators as they seek to use VEGF in treating human conditions characterized by lack of adequate blood flow, such as coronary artery disease or peripheral arterial disease.

Using mice as animal models, the researchers found that exercise initially stimulates the production of VEGF, which then leads to an increase in the number of capillaries within a specific muscle fiber type, ultimately leading to an anaerobic to aerobic change in the muscle fibers supplied by those vessels. The VEGF gene produces a protein that is known to trigger blood vessel growth.

The results of the Duke experiments were presented by cardiologist Richard Waters, M.D., Nov. 8, 2004, at the American Heart Association’s annual scientific sessions in New Orleans.

“It is known that exercise can improve the symptoms of peripheral arterial disease in humans and it has been assumed that angiogenesis played a role in this improvement,” Waters said. “However, the clinical angiogenesis trials to date utilizing VEGF have been marginally successful and largely disappointing, so we felt it would be better at this point to return to animal studies in an attempt to better understand the angiogenic process.”

The Duke team performed their experiments using a mouse model of voluntary exercise. This experimental approach is important, they explained, because most skeletal muscle adaptation studies utilize electrical stimulation of the muscle, which is much less physiologic and does not as closely mimic what would be expected in human exercise.

When placed in the dark with a running wheel, mice will instinctively run, the researchers said. In the Duke experiments, 41 out of 42 mice “ran” up to seven miles each night. At regular intervals over a 28-day period, the researchers then performed detailed analysis of capillary growth and the subsequent changes in muscle fiber type and compared these findings to sedentary mice.

Mammalian muscle is generally made up of two different fiber types – slow-twitch fibers requiring oxygen to function, and the fast-twitch fibers, which function in the absence of oxygen by breaking down glucose. Because of their need for oxygen, slow-twitch fibers tend to have a higher density of capillaries.

“Exercise training is probably the most widely utilized physiological stimulus for skeletal muscle, but the mechanisms underlying the adaptations muscle fibers make in response to exercise is not well understood,” Waters said. “What we have shown in our model is that increases in the capillary density occur before a significant change from fast-twitch to slow-twitch fiber type, and furthermore, that changes in levels of the VEGF protein occur before the increased capillary density.”

“Interestingly, capillary growth appears to occur preferentially among fast-twitch fibers, and it is these very fibers that likely change to slow-twitch fibers,” Waters said. “Since exercise has the potential to impact an enormous number of clinical conditions, therapeutic manipulations intended to alter the response to exercise would benefit from a more detailed understanding of what actually happens to muscle as a result of exercise.”

The exact relationship between VEGF, exercise induced angiogenesis, and muscle fiber type adaptation is still not clear and will become the focus of the group’s continuing research. The findings from the current study, however, are providing important temporal and spatial clues to the adaptability process.

“Our data suggests that angiogenesis is one of the key early steps in skeletal muscle adaptation and may be an essential step in the adaptability process,” Waters continued. “This understanding could be crucial for designing new studies that can be performed to inhibit the angiogenic response to exercise in order to directly test the links between angiogenesis and skeletal muscle plasticity.”

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The research team was supported by grants from the American Heart Association and the U.S. Department of Veterans Affairs.

Other members of the Duke team were Ping Li, Brian Annex, M.D., and Zhen Yan, Ph.D. Svein Rotevatn, Haukeland University Hospital, Bergen, Norway, was also a member of the team.

Duke University Medical Center researchers have identified the skeletal muscle changes that occur in response to endurance exercise and have better defined the role of vascular endothelial growth factor (VEGF) in creating new blood vessels, known as angiogenesis, in the process.

VEGF is a protein known to trigger blood vessel growth by activating numerous genes involved in angiogenesis.

The researchers’ new insights could provide a roadmap for medical investigators as they seek to use VEGF in treating human conditions characterized by lack of adequate blood flow, such as coronary artery disease or peripheral arterial disease.

Using mice as animal models, the researchers found that exercise initially stimulates the production of VEGF, which then leads to an increase in the number of capillaries within a specific muscle fiber type, ultimately leading to an anaerobic to aerobic change in the muscle fibers supplied by those vessels. The VEGF gene produces a protein that is known to trigger blood vessel growth.

The results of the Duke experiments were presented by cardiologist Richard Waters, M.D., Nov. 8, 2004, at the American Heart Association’s annual scientific sessions in New Orleans.

“It is known that exercise can improve the symptoms of peripheral arterial disease in humans and it has been assumed that angiogenesis played a role in this improvement,” Waters said. “However, the clinical angiogenesis trials to date utilizing VEGF have been marginally successful and largely disappointing, so we felt it would be better at this point to return to animal studies in an attempt to better understand the angiogenic process.”

The Duke team performed their experiments using a mouse model of voluntary exercise. This experimental approach is important, they explained, because most skeletal muscle adaptation studies utilize electrical stimulation of the muscle, which is much less physiologic and does not as closely mimic what would be expected in human exercise.

When placed in the dark with a running wheel, mice will instinctively run, the researchers said. In the Duke experiments, 41 out of 42 mice “ran” up to seven miles each night. At regular intervals over a 28-day period, the researchers then performed detailed analysis of capillary growth and the subsequent changes in muscle fiber type and compared these findings to sedentary mice.

Mammalian muscle is generally made up of two different fiber types – slow-twitch fibers requiring oxygen to function, and the fast-twitch fibers, which function in the absence of oxygen by breaking down glucose. Because of their need for oxygen, slow-twitch fibers tend to have a higher density of capillaries.

“Exercise training is probably the most widely utilized physiological stimulus for skeletal muscle, but the mechanisms underlying the adaptations muscle fibers make in response to exercise is not well understood,” Waters said. “What we have shown in our model is that increases in the capillary density occur before a significant change from fast-twitch to slow-twitch fiber type, and furthermore, that changes in levels of the VEGF protein occur before the increased capillary density.”

“Interestingly, capillary growth appears to occur preferentially among fast-twitch fibers, and it is these very fibers that likely change to slow-twitch fibers,” Waters said. “Since exercise has the potential to impact an enormous number of clinical conditions, therapeutic manipulations intended to alter the response to exercise would benefit from a more detailed understanding of what actually happens to muscle as a result of exercise.”

The exact relationship between VEGF, exercise induced angiogenesis, and muscle fiber type adaptation is still not clear and will become the focus of the group’s continuing research. The findings from the current study, however, are providing important temporal and spatial clues to the adaptability process.

“Our data suggests that angiogenesis is one of the key early steps in skeletal muscle adaptation and may be an essential step in the adaptability process,” Waters continued. “This understanding could be crucial for designing new studies that can be performed to inhibit the angiogenic response to exercise in order to directly test the links between angiogenesis and skeletal muscle plasticity.”

 

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Article adapted by MD Sports from original press release.
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Contact: Richard Merritt
Duke University Medical Center 

The research team was supported by grants from the American Heart Association and the U.S. Department of Veterans Affairs

Use, misuse and abuse of drugs shakes foundations of amateur and professional sports?

Baseball team owners, players and fans seem to agree on the importance of drug testing for steroids, according to current reports, but the entire scope of performance-enhancing substances available for all athletes is vastly broader and many of the drugs employed by athletes are not easily detectable, says a Penn State researcher.”The use, misuse and abuse of drugs have long shaken the foundations of amateur and professional sports–baseball, football, track and field, gymnastics and cycling, to name just a few,” says Dr. Charles Yesalis, Penn State professor of exercise and sport science and health policy and administration. “The problem is not new. But like the rest of technology, doping in sport has grown in scientific and ethical complexity. In addition to drugs, we have natural hormones, blood doping, diuretics, nutritional supplements, social and recreational drugs, stimulants and miscellaneous substances, some of which may not even be on any list of banned substances.”

While drug testing technology struggles to keep up, an array of new and emerging technologies has arrived or is on the horizon with potential for abuse by athletes including gene transfer therapy, stem cell transplantation, muscle fiber phenotype transformation, red blood cell substitutes and new drug delivery systems, says Yesalis

“It is not too hard to imagine the day when muscles can be selectively enlarged or contoured,” according to the book. “Just imagine the consequences of a kinesiologist isolating specific muscles and selectively injecting designer genes into those muscles to maximize their function.”

The new book brings together the latest and most comprehensive scientific information about performance-enhancing substances, as well as discussion of drug testing, legal and social issues, and future directions by sports governing organizations.

“Sport has a responsibility to maintain a level playing field for the trial of skill,” Yesalis says. “The use of chemical and pharmacologist agents is cheating – just like using a corked baseball bat. But unlike the bat, doping is shrouded in mystery. Athletes and their advisors are constantly seeking ‘gray areas” surrounding the rules, and if something is not explicitly banned, then why not try it. This slippery slope of rationalization is treacherous and appealing to a player or team seeking glory and money rewards.”

In one chapter, “Drug Testing and Sport and Exercise,” author R. Craig Kammerer suggests that improvement in current tests and developments in new methods will assist future policymaking by athletic federations. However, effective testing must become more widespread and include unannounced testing outside of competition. Sanctions against athletes must be more fairly and uniformly applied, with thorough investigation to avoid false positive results and ruin an athlete’s career.

The difficulty of detecting and preventing the abuse of performance enhancing substances by adult athletes may seem futile but remains necessary as part of the effort to discourage abuse by youths who emulate professional athletes and also seek a winning advantage, Yesalis notes.

A recent government study of adolescent drug use shows an alarming increase in anabolic steroid use among middle school youths from 1998-1999 with an estimated 2.7 percent of eighth graders saying they have used the drugs. A larger survey by Blue Cross and Blue Shield estimates that one million U.S. children between the ages of 12 and 17 may have taken performance-enhancing substances including creatine, according to the book.

“Children and teens can seriously harm their future health by misusing these substances,” Yesalis says. “For example, steroids alone can cause scarring acne, hair loss and testicular atrophy, and may increase the risk of stroke and heart disease. It is just as important to note that little is known about the health consequences of many of the other substances used to enhance performance. Yet some coaches and parents look the other way and even actively encourage the use of performance-enhancing substances in pursuit of scholarships and winning.

“There is too much fame and fortune to be gained by being a winner in sports,” he notes. “It’s interesting to see that baseball fans being polled support drug testing and a ban on steroids, but it will take fans of all major sports to take a stand by turning off their TV sets or not buying a ticket to sports events before adult athletes, coaches and team owners stop trying to cheat. And, that’s probably not going to happen.”

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Article adapted by MD Sports Weblog from original press release.
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Contact: Vicki Fong
Penn State

Scientists encourage genetic research into athletic ability to benefit sport and public health

Genetic research into athletic ability should be encouraged for its potential benefits in both sport and public health, a leading group of scientists meeting at the University of Bath said today. Genetic research into athletic ability should be encouraged for its potential benefits in both sport and public health, a leading group of scientists meeting at the University of Bath said today.

However, ethical concerns, such as whether seeking information about differences between ethnic groups could be perceived as racist research, need to be properly addressed, they warn.

Their recommendations are published in a ‘position stand’ on genetic research and testing launched at the British Association of Sport & Exercise Sciences annual meeting today.

They call for more genetic research in the sport and exercise sciences because of the anticipated benefits for public health, but want researchers to take a more active role in debating the implications of their work with the public.

“If a powerful muscle growth gene was identified, on the one hand this could help develop training programmes that increase muscle size and strength in athletes, but even more importantly the knowledge could be used to develop exercise programmes or drugs to combat muscle wasting in old age,” said Dr Alun Williams from Manchester Metropolitan University, one of the report’s authors.

“We, as scientists investigating genetics, acknowledge a public concern about some genetic research and we believe scientists need to engage in public in debates about the potential benefits of their research.

“Research into the athletic success of East African distance runners or sprinters of West African ancestry might be perceived as unethical.

“But understanding the limits of human exercise capacity in sport could lead to the development of treatments for a range of diseases like cancer and cardiovascular disease.”

The potential applications of genetic testing in sport and exercise also raise some ethical concerns, for example in identifying potential athletic ability before birth.

An Australian company already offers the first genetic performance test (for the ACTN3 gene) which has been linked to sprint and power performance.

The report authors are sceptical about whether this test is useful but anticipate that more advanced versions of these tests will be available in future.

“We are not yet at a point where we can identify a potential future Olympic champion from genetic tests but we may not be very far away,” said Dr Williams, who wrote the report with Drs Henning Wackerhage (Aberdeen University), Andy Miah (University of Paisley), Roger Harris (University of Chichester) and Hugh Montgomery (University College London).

They highlight two dangers of genetic performance tests. Firstly, genetic performance tests might later be linked to disease. For example, a muscle growth gene may later be linked to cancer growth.

“Not all people may want to know, while young that they are at increased risk of cancer by early middle age, but they might inadvertently become aware of that just because they had a ‘sport gene’ test,” said Dr Williams.

Secondly, genetic performance tests can be performed even before birth and this may lead to the selection of foetuses or to abortions based on athletic potential.

The report recommends genetic counselling and that the testing should be confined to mature individuals who fully understand the relevant issues.

Genetic tests might also be used to screen for health risks during sport such as genes that are linked to sudden cardiac death.

Genetic tests for sudden cardiac death are already available but the report recommends that such testing should not be enforced on athletes.

Problems with mandatory testing are highlighted by the case of the basketball player Eddy Curry, who had an irregular heart beat.

Curry was asked by his club, the Chicago Bulls, to perform a predictive genetic test for a heart condition. The athlete refused and was traded to the New York Knicks who did not make such a demand.

In future, genetic tests might be used to identify those that respond with the biggest drop in cholesterol, blood pressure or glucose to exercise.

In a personalised medicine approach, such tests could be used to select subjects for therapeutic exercise programmes but scientists are concerned that this might undermine the ‘exercise for all’ message that already seems difficult to get across to the public.

The authors say that genetic testing might also be used to detect gene doping, which may be a real threat by the time of the London Olympics in 2012, or to show that positive doping tests are the result of a genetic mutation in an athlete.

The report recommends that genetic testing should be used for anti-doping testing as long as the genetic samples are destroyed after testing.

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Article adapted by MD Sports Weblog from original press release.
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Contact: Andrew McLaughlin
University of Bath

Gene mutation linked to increased athletic performance

Whippets are bred for speed and have been clocked at speeds approaching 40 miles per hour over a 200-yard racing course. Scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), have now discovered a genetic mutation that helps to explain why some whippets run even faster than others. Published in the open-access journal PLoS Genetics, their findings will make for a fascinating experiment in applied genetics and human nature: what will dog breeders do with this information, and what are the implications for human athletic performance?

A research team led by Elaine Ostrander, chief of the Cancer Genetics Branch in NHGRI’s Division of Intramural Research, reports that a mutation in a gene that codes for a muscle protein known as myostatin can increase muscle mass and enhance racing performance in whippets. Like humans, dogs have two copies of every gene, one inherited from their mother and the other from their father. Dr. Ostrander and colleagues found those whippets with one mutated copy of the myostatin (MTSN) gene and one normal copy to be more muscled than normal and are among the breed’s fastest racers. However, their research also showed that whippets with two mutated copies of the MTSN gene have a gross excess of muscle and are rarely found among competitive racers.

This is the first work to link athletic performance to a mutation in the myostatin gene, with Dr. Ostrander observing: “The potential to increase an athlete’s performance by disrupting MSTN either by natural or perhaps artificial means could change the face of competitive human and canine athletics.” However, the authors stress that: “Extreme caution should be exercised when acting upon these results because we do not know the consequences for overall health associated with myostatin mutations.”

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Article adapted by MD Sports Weblog from original press release.
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Contact: Johanna Dehlinger
Public Library of Science

CITATION: Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, et al. (2007) A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs. PLoS Genet. doi:10.1371/journal.pgen.0030079.eor
 

Stunning discovery may make Blood-Doping as easy as washing hair

A stunning discovery by German scientists may make blood doping and the treatment of severe anemia as easy as washing your hair.  

In the October print issue of The FASEB Journal (http://www.fasebj.org/), researchers show that the estimated 100,000 hair follicles on each person’s head have the potential to become erythropoietin (EPO) factories. EPO, the hormone primarily responsible for the creation of red blood cells, is used illegally to enhance athletic performance and is used legally to treat severe anemia associated with kidney failure and chemotherapy.

“The ultimate hope is that we’ll be able to up the production of natural EPO in our hair follicles whenever we need it, safely and at a low cost,” said Ralf Paus, senior author of the study. “Our study also highlights that ancient hormones are engaged in many more activities than conventional medical wisdom has assigned to them.”

Normally, EPO is created and released by the kidneys. When the kidneys fail, or when someone undergoes chemotherapy, this process is disrupted and severe anemia occurs. Today, most people are treated using synthetic EPO to bring red blood cells back to normal levels, but synthetic versions of this hormone are relatively expensive. Blood-doping athletes use synthetic EPO to help their bodies bring red blood cells to above-normal levels. This increased concentration of red blood cells allows the blood to deliver more oxygen to muscles than normal, significantly improving endurance and performance. The major danger in boosting the number of red blood cells above normal is that as the blood thickens with red blood cells, the possibility of heart attack increases.

“This study opens doors to an entirely new approach for treating EPO-related anemia,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “The study also is important because it suggests that there is still much to learn about ‘well known’ processes in the body.”

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Article adapted by MD Sports Weblog from original press release.
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Source: Cody Mooneyhan
Federation of American Societies for Experimental Biology

The FASEB Journal (http://www.fasebj.org/) is published by the Federation of American Societies for Experimental Biology (FASEB) and is consistently ranked among the top three biology journals worldwide by the Institute for Scientific Information. FASEB comprises 21 nonprofit societies with more than 80,000 members, making it the largest coalition of biomedical research associations in the United States. FASEB advances biological science through collaborative advocacy for research policies that promote scientific progress and education and lead to improvements in human health.