Archive for December 3, 2007

The Johns Hopkins scientists who first created “mighty mice” have developed, with pharmaceutical company Wyeth and the biotechnology firm MetaMorphix, an agent that’s more effective at increasing muscle mass in mice than a related potential treatment for muscular dystrophy now in clinical trials.

The new agent is a version of a cellular docking point for the muscle-limiting protein myostatin. In mice, just two weekly injections of the new agent triggered a 60 percent increase in muscle size, the researchers report in the Proceedings of the National Academy of Sciences, published and available publicly through the journal’s website.

The researchers’ original mighty mice, created by knocking out the gene that codes for myostatin, grew muscles twice as big as normal mice. An antibody against myostatin now in clinical trials caused mice to develop muscles 25 percent larger than those of untreated mice after five weeks or more of treatment.

The researchers’ expectation is that blocking myostatin might help maintain critical muscle strength in people whose muscles are wasting due to diseases like muscular dystrophy or side effects from cancer treatment or AIDS.

“This new inhibitor of myostatin, known as ACVR2B, is very potent and gives very dramatic effects in the mice,” says Se-Jin Lee, M.D., Ph.D., a professor of molecular biology and genetics in Johns Hopkins’ Institute for Basic Biomedical Sciences. “Its effects were larger and faster than we’ve seen with any other agent, and they were even larger than we expected.”

ACVR2B is the business end of a cellular docking point for the myostatin protein, and it probably works in part by mopping up myostatin so it can’t exert its muscle-inhibiting influence. But the researchers’ experiments also show that the new agent’s extra potency stems from its ability to block more than just myostatin, says Lee.

“We don’t know how many other muscle-limiting proteins there may be or which ones they are,” says Lee, “but these experiments clearly show that myostatin is not the whole story.”

The evidence for other players came from experiments with mighty mice themselves. Because these mice don’t have any myostatin, any effects of injecting the new agent would come from its effects on other proteins, explains Lee. After five injections over four weeks, mighty mice injected with the new agent had muscles 24 percent larger than their counterparts that didn’t get the new agent.

“In some ways this was supposed to be a control experiment,” says Lee. “We weren’t really expecting to see an effect, let alone an effect that sizeable.”

In other experiments with normal female mice, weekly injections of the new agent provided the biggest effect on muscle growth after just two weeks at the highest dose given (50 milligrams per kilogram mouse weight). Depending on the muscle group analyzed, the treated mice’s muscles were bigger than untreated mice by 39 percent (the gastrocnemius [calf] muscle) to 61 percent (the triceps).

After just one week, mice given a fifth of that highest dose had muscles 16 percent to 25 percent bigger than untreated mice, depending on the muscle group analyzed, and mice treated with one injection a week for two, three or four weeks continued to gain muscle mass.

But although the new agent seems quite promising, its advantage in potency also requires extra caution. “We don’t know what else the new agent is affecting or whether those effects will turn out to be entirely beneficial,” says Lee.

Lee says they also are conducting experiments with the mice now to see whether the effect lasts after injections cease and whether it helps a mouse model of muscular dystrophy retain enough muscle strength to prolong life.

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Article adapted by MD Sports Weblog from original press release.
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Contact: Joanna Downer
Johns Hopkins Medical Institutions

The research was funded by grants from the National Institute of Child Health and Human Development and the National Cancer Institute and by funds from Wyeth Research and MetaMorphix Inc. The new agent was produced and first tested at Wyeth, and the inhibitor used in the current mouse studies was produced at MetaMorphix. All of the mouse studies described in this article and in the PNAS paper were conducted in Lee’s laboratory at Johns Hopkins.

Authors on the report are Se-Jin Lee and Suzanne Sebald of Johns Hopkins; Lori Reed of Wyeth Exploratory Drug Safety, and Monique Davies, Stefan Girgenrath, Mary Goad, Kathy Tomkinson, Jill Wright and Neil Wolfman of Wyeth Discovery Research; Christopher Barker, Gregory Ehrmantraut, James Holmstrom and Betty Trowell of MetaMorphix Canada; Barry Gertz, Man-Shiow Jiang, Li-fang Liang, Edwin Quattlebaum and Ronald Stotish of MetaMorphix, Beltsville, Md.; Martin Matzuk of Baylor College of Medicine; and En Li of Harvard Medical School.

Myostatin was licensed by The Johns Hopkins University to MetaMorphix and sublicensed to Wyeth. Lee is entitled to a share of sales royalty received by The Johns Hopkins University from sales of this factor. The Johns Hopkins University and Lee also own MetaMorphix stock, which is subject to certain restrictions under university policy. Lee is a paid consultant to MetaMorphix. The terms of these arrangements are being managed by the university in accordance with its conflict of interest policies.

On the Web: http://www.pnas.org/cgi/content/abstract/0505996102v1

Researchers at the University of Pennsylvania say that practicing even small doses of daily meditation may improve focus and performance.

Meditation, according to Penn neuroscientist Amishi Jha and Michael Baime, director of Penn’s Stress Management Program, is an active and effortful process that literally changes the way the brain works. Their study is the first to examine how meditation may modify the three subcomponents of attention, including the ability to prioritize and manage tasks and goals, the ability to voluntarily focus on specific information and the ability to stay alert to the environment.

In the Penn study, subjects were split into two categories. Those new to meditation, or “mindfulness training,” took part in an eight-week course that included up to 30 minutes of daily meditation. The second group was more experienced with meditation and attended an intensive full-time, one-month retreat.

Researchers found that even for those new to the practice, meditation enhanced performance and the ability to focus attention. Performance-based measures of cognitive function demonstrated improvements in a matter of weeks. The study, published in the journal Cognitive, Affective, & Behavioral Neuroscience, suggests a new, non-medical means for improving focus and cognitive ability among disparate populations and has implications for workplace performance and learning.

Participants performed tasks at a computer that measured response speeds and accuracy. At the outset, retreat participants who were experienced in meditation demonstrated better executive functioning skills, the cognitive ability to voluntarily focus, manage tasks and prioritize goals. Upon completion of the eight-week training, participants new to meditation had greater improvement in their ability to quickly and accurately move and focus attention, a process known as “orienting.” After the one-month intensive retreat, participants also improved their ability to keep attention “at the ready.”

The results suggest that meditation, even as little as 30 minutes daily, may improve attention and focus for those with heavy demands on their time. While practicing meditation may itself may not be relaxing or restful, the attention-performance improvements that come with practice may paradoxically allow us to be more relaxed.

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Article adapted by MD Sports Weblog from original press release.
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Contact: Jordan Reese
University of Pennsylvania

The research was supported by the National Institutes of Health and the Penn Stress Management Program.

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

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