Posts Tagged ‘myostatin’

University of Pittsburgh School of Medicine researchers have successfully used gene therapy to accelerate muscle regeneration in experimental animals with muscle damage, suggesting this technique may be a novel and effective approach for improving skeletal muscle healing, particularly for serious sports-related injuries. These findings are being presented at the American Society of Gene Therapy annual meeting in Baltimore, May 31 to June 4.

Skeletal muscle injuries are the most common injuries encountered in sports medicine. Although such injuries can heal spontaneously, scar tissue formation, or fibrosis, can significantly impede this process, resulting in incomplete functional recovery. Of particular concern are top athletes, who, when injured, need to recover fully as quickly as possible.
In this study, the Pitt researchers injected mice with a gene therapy vector containing myostatin propeptide–a protein that blocks the activity of the muscle-growth inhibitor myostatin–three weeks prior to experimentally damaging the mice’s skeletal muscles. Four weeks after skeletal muscle injury, the investigators observed an enhancement of muscle regeneration in the gene-therapy treated mice compared to the non-gene-therapy treated control mice. There also was significantly less fibrous scar tissue in the skeletal muscle of the gene-therapy treated mice compared to the control mice.
According to corresponding author Johnny Huard, Ph.D., the Henry J. Mankin Endowed Chair and Professor in Orthopaedic Surgery, University of Pittsburgh School of Medicine, and Director of the Stem Cell Research Center of Children’s Hospital of Pittsburgh, this approach offers a significant, long-lasting method for treating serious, sports-related muscle injuries.
“Based on our previous studies, we expect that gene-therapy treated cells will continue to overproduce myostatin propeptide for at least two years. Since the remodeling phase of skeletal muscle healing is a long-term process, we believe that prolonged expression of myostatin propeptide will continue to contribute to recovery of injured skeletal muscle by inducing an increase in muscle mass and minimizing fibrosis. This could significantly reduce the amount of time an athlete needs to recover and result in a more complete recovery,” he explained.
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Others involved in this study include, Jinhong Zhu, M.D., Yong Li, M.D., Ph.D., of the Growth and Development Laboratory, Children’s Hospital of Pittsburgh; and Chunping Qiao, M.D., and Xiao Xiao, M.D., Ph.D., of the Molecular Therapies Laboratory, department of orthopaedic surgery, University of Pittsburgh School of Medicine.
University of Pittsburgh School of Medicine researchers have successfully used gene therapy to accelerate muscle regeneration in experimental animals with muscle damage, suggesting this technique may be a novel and effective approach for improving skeletal muscle healing, particularly for serious sports-related injuries.
Skeletal muscle injuries are the most common injuries encountered in sports medicine. Although such injuries can heal spontaneously, scar tissue formation, or fibrosis, can significantly impede this process, resulting in incomplete functional recovery. Of particular concern are top athletes, who, when injured, need to recover fully as quickly as possible.
In this study, the Pitt researchers injected mice with a gene therapy vector containing myostatin propeptide–a protein that blocks the activity of the muscle-growth inhibitor myostatin–three weeks prior to experimentally damaging the mice’s skeletal muscles. Four weeks after skeletal muscle injury, the investigators observed an enhancement of muscle regeneration in the gene-therapy treated mice compared to the non-gene-therapy treated control mice. There also was significantly less fibrous scar tissue in the skeletal muscle of the gene-therapy treated mice compared to the control mice.
According to corresponding author Johnny Huard, Ph.D., the Henry J. Mankin Endowed Chair and Professor in Orthopaedic Surgery, University of Pittsburgh School of Medicine, and Director of the Stem Cell Research Center of Children’s Hospital of Pittsburgh, this approach offers a significant, long-lasting method for treating serious, sports-related muscle injuries.
“Based on our previous studies, we expect that gene-therapy treated cells will continue to overproduce myostatin propeptide for at least two years. Since the remodeling phase of skeletal muscle healing is a long-term process, we believe that prolonged expression of myostatin propeptide will continue to contribute to recovery of injured skeletal muscle by inducing an increase in muscle mass and minimizing fibrosis. This could significantly reduce the amount of time an athlete needs to recover and result in a more complete recovery,” he explained.
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Article adapted by MD Sports from original press release.
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Contact: Jim Swyers

Others involved in this study include, Jinhong Zhu, M.D., Yong Li, M.D., Ph.D., of the Growth and Development Laboratory, Children’s Hospital of Pittsburgh; and Chunping Qiao, M.D., and Xiao Xiao, M.D., Ph.D., of the Molecular Therapies Laboratory, department of orthopaedic surgery, University of Pittsburgh School of Medicine.

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By studying the genes of a German child born with unusually well developed muscles, an international research team has discovered the first evidence that the gene whose loss makes “mighty mice” also controls muscle growth in people.

Writing in the June 24 issue of the New England Journal of Medicine, German neurologist Markus Schuelke, M.D., and the team show that the child’s extra-large muscles are due to an inherited mutation that effectively silences the myostatin gene, proving that its protein normally keeps muscle development in check in people.

People with muscle-wasting conditions such as muscular dystrophy, and others just wanting to “bulk up,” have eagerly followed work on myostatin, hoping for a way to counteract the protein’s effects in order to build or rebuild muscle mass. But while research with mice has continued to reveal myostatin’s role and the effects of interfering with it, no one knew whether any of the results would be relevant to humans.

“This is the first evidence that myostatin regulates muscle mass in people as it does in other animals,” says Se-Jin Lee, M.D., Ph.D., professor of molecular biology and genetics in the Institute for Basic Biomedical Sciences at Johns Hopkins and co-author on the study. “That gives us a great deal of hope that agents already known to block myostatin activity in mice may be able to increase muscle mass in humans, too.”

Lee and his team discovered in 1997 that knocking out the myostatin gene led to mice that were twice as muscular as their normal siblings, lending them the moniker “mighty mice.” Later, others showed that naturally bulky cattle, such as Belgian Blues, got their extra muscles from lack of myostatin, too.

An unusual opportunity to examine myostatin’s role in humans arose when Schuelke examined a newborn baby boy, almost five years ago, and was struck by the visible muscles on the infant’s upper legs and upper arms. When ultrasound proved that the muscles were roughly twice as large as other infants’, but otherwise normal, Schuelke realized that a naturally occurring mutation in the child’s myostatin gene might be the cause.

Sequencing the myostatin gene from the boy and his mother, who had been a professional athlete, revealed a single change in the building blocks of the gene’s DNA. Surprisingly, the change was not in the gene regions that correspond to the resulting protein, but in the intervening regions that are used only to create protein-making instructions, thus changing the gene’s protein-building message.

“The mutation caused the gene’s message, the messenger RNA, to be wrong,” says Hopkins

neurologist Kathryn Wagner, M.D., Ph.D., who tested the genetic mutation’s effect in laboratory studies. “If the message had been used to make a protein, it would be much shorter than it should be. But we think the process doesn’t even get that far; instead the cells just destroy the message.”

Co-authors from Wyeth Research, Cambridge, Mass., analyzed samples of the child’s blood for evidence of the myostatin protein and found none. “Both copies of the child’s myostatin gene have this mutation, so little if any of the myostatin protein is made,” says Schuelke. “As a result, he has about twice the muscle mass of other children.”

Completely lacking myostatin, the boy is stronger than other children his age, and fortunately has no signs of problems with his heart so far, Schuelke says. But he adds that it’s impossible to know whether the lack of myostatin in that crucial muscle might lead to problems as the boy gets older.

While other family members — the boy’s mother and her brother, father and grandfather — were also reported to have been usually strong, only the mother’s DNA was available for analysis along with her son’s. Schuelke discovered that only one copy of the mother’s myostatin gene had the mutation found in both copies of her son’s myostatin gene. (We have two copies of each gene; one inherited from the mother and one inherited from the father.)

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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 Johns Hopkins researchers were funded by the National Institutes of Health and the Muscular Dystrophy Association. The German researchers were funded by the parents’ self-help group (Helft dem muskelkranken Kind).

Authors on the paper are Schuekle, Christoph Hubner, Thomas Riebel and Wolfgang Komen of Charite, University Medical Center Berlin, Germany; Wagner and Lee of Johns Hopkins; Leslie Stolz and James Tobin of Wyeth Research, Cambridge, Ma.; and Thomas Braun of Martin-Luther-University, Halle-Wittenberg, Germany.

*Under a licensing agreement between MetaMorphix Inc. and The Johns Hopkins University, Lee is entitled to a share of royalty received by the University on sales of products described in this article. Lee also is entitled to a share of sublicensing income from arrangements between MetaMorphix and American Home Products (Wyeth Ayerst Laboratories) and Cape Aquaculture Technologies. Lee and the University own MetaMorphix Inc. stock, which is subject to certain restrictions under University policy. Lee owns Cape Aquaculture Technologies stock, which is subject to certain restrictions under University policy. Lee has served as a paid consultant to MetaMorphix Inc. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

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

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