New Cause of Muscular Dystrophies Reveals How Muscles Mass Increases

“No pain, no gain.” So say those working out to build up their muscles, and on a cellular level it is a pretty accurate description of how muscle mass increases. Exercise causes tears in muscle membrane and the healing process produces an increased amount of healthy muscle. Implicit in this scenario is the notion that muscle repair is an efficient and ongoing process in healthy individuals. However, the repair process is not well understood. New University of Iowa research into two types of muscular dystrophy now has opened the door on a muscle repair process and identified a protein that plays a critical role.

The protein, called dysferlin, is mutated in two distinct muscular dystrophies known as Miyoshi Myopathy and limb-girdle muscular dystrophy type 2b. The UI study suggests that in these diseases, the characteristic, progressive muscle degeneration is due to a faulty muscle-repair mechanism rather than an inherent weakness in the muscle’s structural integrity. The research findings reveal a totally new cellular cause of muscular dystrophy and may lead to many discoveries about normal muscle function and to therapies for muscle disorders.

The research team led by Kevin Campbell, Ph.D., the Roy J. Carver Chair of Physiology and Biophysics and interim head of the department, UI professor of neurology, and a Howard Hughes Medical Institute (HHMI) Investigator, studied the molecular consequences of losing dysferlin and discovered that without dysferlin muscles were unable to heal themselves.

The UI team genetically engineered mice to lack the dysferlin gene. Just like humans with Miyoshi Myopathy and limb-girdle muscular dystrophy type 2b, the mice developed a muscular dystrophy, which gets progressively worse with age. However, treadmill tests revealed that the muscles of mice that lack dysferlin were not much more susceptible to damage than the muscles of normal mice. This contrasts with most muscular dystrophies of known cause where genetic mutations weaken muscle membranes and make muscles more prone to damage.

“This told us that the dystrophies caused by dysferlin loss were very different in terms of how the disease process works compared to other dystrophies we have studied,” Campbell said. “We were gradually picking up clues that showed we had a different type of muscular dystrophy here.”

Most muscular dystrophy causing genetic mutations have been linked to disruption of a large protein complex that controls the structural integrity of muscle cells. The researchers found that dysferlin was not associated with this large protein complex. Rather, dysferlin is normally found throughout muscle plasma membrane and also in vesicles, which are small membrane bubbles that encapsulate important cellular substances and ferry them around cells. Vesicles also are important for moving membrane around in cells.

Previous studies have shown that resealing cell membranes requires the accumulation and fusing of vesicles to repair the damaged site.

Using an electron microscope to examine muscles lacking dysferlin, the UI team found that although vesicles gathered at damaged membrane sites, the membrane was not resealed. In contrast, the team discovered that when normal muscle is injured, visible “patches” form at the damaged sites, which seal the holes in the membrane. Chemicals that tag dysferlin proved that these “patches” were enriched with dysferlin and the patches appeared to be formed by the fusion of dysferlin-containing vesicles that traveled though the cell to the site of membrane damage.

The researchers then used a high-powered laser and a special dye to visualize the repair process in real time.

Under normal conditions, the dye is unable to penetrate muscle membrane. However, if the membrane is broken the dye can enter the muscle fiber where it fluoresces. Using the laser to damage a specific area of muscle membrane, the researchers could watch the fluorescence increase as the dye flowed into the muscle fiber.

“The more dye that entered, the more fluorescence we saw,” Campbell explained. “However, once the membrane was repaired, no more dye could enter and the level of fluorescence remained steady. Measuring the increase in fluorescence let us measure the amount of time that the membrane stayed open before repair sealed the membrane and prevented any more dye from entering.”

In the presence of calcium, normal membrane repaired itself in about a minute. In the absence of calcium, vesicles gathered at the damaged muscle membrane, but they did not fuse with each other or with the membrane and the membrane was not repaired. In muscle that lacked dysferlin, even in the presence of calcium, the damaged site was not repaired.

Campbell speculated that dysferlin, which contains calcium-binding regions, may be acting as a calcium sensor and that the repair system needs to sense the calcium in order to initiate the fusion and patching of the hole. Campbell added that purifying the protein and testing its properties should help pin down its role in the repair process.

The discovery of a muscle repair process and of dysferlin’s role raises many new questions. In particular, Campbell wonders what other proteins might be involved and whether defects in those components could be the cause of other muscular dystrophies.

“This work has described a new physiological mechanism in muscle and identified a component of this repair process,” Campbell said. “What is really exciting for me is the feeling that this is just a little hint of a much bigger picture.”

In addition to Campbell, the UI researchers included Dimple Bansal, a graduate student in Campbell’s laboratory and the lead author of the paper, Severine Groh, Ph.D., and Chien-Chang Chen, Ph.D., both UI post-doctoral researchers in physiology and biophysics and neurology, and Roger Williamson, M.D., UI professor of obstetrics and gynecology. Also part of the research team were Katsuya Miyake, Ph.D., a postdoctoral researcher, and Paul McNeil, Ph.D., a professor of cellular biology and anatomy at the Medical College of Georgia in Augusta, Ga., and Steven Vogel, Ph.D., at the Laboratory of Molecular Physiology at the National Institute of Alcohol Abuse and Alcoholism, Rockville, Md.

———————————–
Article adapted by MD Sports from original press release.
———————————–

Contact: Jennifer Brown
University of Iowa 

The study was funded by a grant from the Muscular Dystrophy Association.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide.

Body chemical ‘switch’ turns muscle atrophy on

 

Researchers in Purdue University’s School of Veterinary Medicine have discovered genetic and drug-treatment methods to arrest the type of muscle atrophy often caused by muscle disuse, as well as aging and diseases such as cancer.

The findings might eventually benefit people who have been injured or suffer from diseases that cause them to be bedridden and lose muscle mass, or sometimes limbs, due to atrophy, said Amber Pond, a research scientist in the school’s Department of Basic Medical Sciences.

“The weight loss and muscle wasting that occurs in patients with cancer or other diseases seriously compromises their well-being and is correlated with a poor chance for recovery,” Pond said. “In addition, muscle weakness caused by atrophy during aging can lead to serious falls and bone loss. Exercise is the most beneficial strategy to treat atrophy. However, many individuals are too ill to adequately participate in exercise programs.

“We’ve found a chemical ‘switch’ in the body that allows us to turn atrophy on, and, from that, we also have learned how to turn atrophy off.”

Findings based on the research, funded in large part by the American Heart Association, are detailed in a study available online today (Wednesday, May 24) in The FASEB Journal, published by the Federation of American Societies for Experimental Biology. The study will be in the journal’s print edition in July.

The research team found atrophy of skeletal muscle in mice could be inhibited with both gene therapy and drug treatment using astemizole (as-TEM-uh-zole), an antihistamine. This new insight has potential in many different areas of research, Pond said.

“We have discovered a direct link between atrophy and a protein in the skeletal muscle,” Pond said. “This led us to develop methods that would block the protein’s ability to cause atrophy. Through drug treatment, we were able to block atrophy, allowing muscle to retain 97 percent of its original fiber size in the face of atrophy.”

Astemizole, which was withdrawn from the market in 2000 because of its potential to cause serious cardiovascular problems, wouldn’t be suitable for use in humans, Pond said. The drug can be used in mice because it doesn’t affect their hearts to the same extent.

“Astemizole administration to humans poses too great a risk,” Pond said. “There’s a need for more study to avoid those side effects, but the key is that we found a protein capable of sensing muscle disuse and initiating atrophy.”

In the drug study, researchers used four groups of mice: a control group, a second group that was given astemizole, and two additional groups in which muscle atrophy was introduced. One of these two groups received astemizole while the second did not. Both of these groups were placed in cages constructed to elevate them so that they were unable to place any weight on their back legs.

“Use of the custom cages to produce atrophy was established in the ’80s for simulation of NASA space flight; you can’t mimic these effects on muscle and bone in cell culture,” said Kevin Hannon, associate professor of developmental anatomy and one of the study’s authors. “The mice were able to move around the cage and eat and drink on their own. We monitored their food and water intake and overall health and ensured that they were playing and eating normally.”

This method allowed the scientists to demonstrate the effects of skeletal muscle atrophy and investigate reasons for the link with the Merg1a protein. The Merg1a protein is a channel that normally passes a small electrical current across the cell.

The researchers implanted a gene into the skeletal muscle that resulted in a mutant form of this protein that combines with the normal protein and stops the current. The researchers found that the mutant protein would inhibit atrophy in mice whose ability to use their back legs was limited.

Because gene therapy is not yet a practical treatment option in humans, the researchers decided to go a step further and stop the function of the protein with astemizole, which is a known “Merg1a channel blocker.” The researchers found that the drug produced basically the same results as the gene therapy. In fact, muscle size increased in mice in the group that were given the drug without any other treatment.

“We are now looking at the differences in the structure of the heart and the skeleton to give us clues on how to specifically target muscles without the cardiac side effects,” Pond said.

###

This research also was partially supported by the U.S. Department of Agriculture and Purdue’s basic medical sciences department.

Writer: Maggie Morris, (765) 494-2432, maggiemorris@purdue.edu

Sources: Amber Pond, (765) 494-6185, pond@purdue.edu 

Kevin Hannon, (765) 494-5949, hannonk@purdue.edu

Related Web sites: 

Purdue School of Veterinary Medicine: http://www.vet.purdue.edu/ 

FASEB Journal: http://www.fasebj.org/ 

STORY AND PHOTO CAN BE FOUND AT: http://news.uns.purdue.edu/UNS/html4ever/2006/060524.Pond.atrophy.html

Researchers in Purdue University’s School of Veterinary Medicine have discovered genetic and drug-treatment methods to arrest the type of muscle atrophy often caused by muscle disuse, as well as aging and diseases such as cancer.

The findings might eventually benefit people who have been injured or suffer from diseases that cause them to be bedridden and lose muscle mass, or sometimes limbs, due to atrophy, said Amber Pond, a research scientist in the school’s Department of Basic Medical Sciences.

“The weight loss and muscle wasting that occurs in patients with cancer or other diseases seriously compromises their well-being and is correlated with a poor chance for recovery,” Pond said. “In addition, muscle weakness caused by atrophy during aging can lead to serious falls and bone loss. Exercise is the most beneficial strategy to treat atrophy. However, many individuals are too ill to adequately participate in exercise programs.

“We’ve found a chemical ‘switch’ in the body that allows us to turn atrophy on, and, from that, we also have learned how to turn atrophy off.”

Findings based on the research, funded in large part by the American Heart Association, are detailed in a study available online today (Wednesday, May 24) in The FASEB Journal, published by the Federation of American Societies for Experimental Biology. The study will be in the journal’s print edition in July.

The research team found atrophy of skeletal muscle in mice could be inhibited with both gene therapy and drug treatment using astemizole (as-TEM-uh-zole), an antihistamine. This new insight has potential in many different areas of research, Pond said.

“We have discovered a direct link between atrophy and a protein in the skeletal muscle,” Pond said. “This led us to develop methods that would block the protein’s ability to cause atrophy. Through drug treatment, we were able to block atrophy, allowing muscle to retain 97 percent of its original fiber size in the face of atrophy.”

Astemizole, which was withdrawn from the market in 2000 because of its potential to cause serious cardiovascular problems, wouldn’t be suitable for use in humans, Pond said. The drug can be used in mice because it doesn’t affect their hearts to the same extent.

“Astemizole administration to humans poses too great a risk,” Pond said. “There’s a need for more study to avoid those side effects, but the key is that we found a protein capable of sensing muscle disuse and initiating atrophy.”

In the drug study, researchers used four groups of mice: a control group, a second group that was given astemizole, and two additional groups in which muscle atrophy was introduced. One of these two groups received astemizole while the second did not. Both of these groups were placed in cages constructed to elevate them so that they were unable to place any weight on their back legs.

“Use of the custom cages to produce atrophy was established in the ’80s for simulation of NASA space flight; you can’t mimic these effects on muscle and bone in cell culture,” said Kevin Hannon, associate professor of developmental anatomy and one of the study’s authors. “The mice were able to move around the cage and eat and drink on their own. We monitored their food and water intake and overall health and ensured that they were playing and eating normally.”

This method allowed the scientists to demonstrate the effects of skeletal muscle atrophy and investigate reasons for the link with the Merg1a protein. The Merg1a protein is a channel that normally passes a small electrical current across the cell.

The researchers implanted a gene into the skeletal muscle that resulted in a mutant form of this protein that combines with the normal protein and stops the current. The researchers found that the mutant protein would inhibit atrophy in mice whose ability to use their back legs was limited.

Because gene therapy is not yet a practical treatment option in humans, the researchers decided to go a step further and stop the function of the protein with astemizole, which is a known “Merg1a channel blocker.” The researchers found that the drug produced basically the same results as the gene therapy. In fact, muscle size increased in mice in the group that were given the drug without any other treatment.

“We are now looking at the differences in the structure of the heart and the skeleton to give us clues on how to specifically target muscles without the cardiac side effects,” Pond said.

———————————–
Article adapted by MD Sports from original press release.
———————————–

Contact: Maggie Morris
Purdue University 

This research also was partially supported by the U.S. Department of Agriculture and Purdue’s basic medical sciences department.

Related Web sites: 
Purdue School of Veterinary Medicine: http://www.vet.purdue.edu/ 
FASEB Journal: http://www.fasebj.org/ 

Rebuilding of skeletal muscle accelerated by Gene therapy

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.

###

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.

———————————–
Article adapted by MD Sports from original press release.
———————————–

Contact: Jim Swyers

University of Pittsburgh Medical Center 

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.

Testosterone Supplements For Elderly Could Improve Strength

The University of Manchester is investigating whether increasing the testosterone levels of frail elderly men could improve their strength, energy and mobility.

This is the first study in the world to examine how testosterone treatment may impact this age-group, led by Professor Fred Wu of the Department of Endocrinology at Manchester Royal Infirmary.

Professor Wu said: “Levels of the male hormone testosterone fall by about 1% a year in men over 40, leading to decreases in muscle size and strength, increased body fat and thinner bones. The changes are also associated with decreased sexual interest, fatigue, mobility problems, depression, increased risk of falling and a general sense of weakness.

“Tests on younger and healthy older men suggest that testosterone replacement could help reverse these symptoms in the frail and elderly.”

Professor Wu’s team is expecting to publish the results in two years’ time, and hopes that if the treatment is proven to be effective it may be adopted as standard practice by the NHS.

As well as increasing strength, mobility and quality of life for elderly men, the move could significantly reduce the accident-rate and care requirements of this group and ultimately reduce demands on the NHS and social services.

Men aged 65+ who have lost weight, are easily tired, slow in walking and feel generally weak for no specific reason are being recruited for the study. Only those volunteers found to have low testosterone levels can be included in the trial.

The protocol for participants requires five visits to the Wellcome Trust Clinical Research Facility on Grafton Street at Manchester Royal Infirmary over the 12 month period. They will receive either testosterone or a dummy placebo in the form of a gel self-applied daily to the skin, for the first six months of the trial. Their muscle strength, mobility, bone-strength, muscle and fat content and general quality of life will then be assessed by the research team after both six and 12 months.

The research is being undertaken in partnership with Central Manchester and Manchester Children’s University Hospitals NHS Trust. Participants are free to withdraw from the study at any time, and all information will be collected in the strictest confidence.

———————————–
Article adapted by MD Sports from original press release.
———————————–

Contact: Jo Nightingale or Rachael McGraw
University of Manchester

NOTES FOR EDITORS

The University of Manchester (www.manchester.ac.uk) was formed by the merger of The Victoria University of Manchester and UMIST in October 2004, and with 36,000 students is the largest higher education institution in the country. Its Faculty of Medical & Human Sciences (www.mhs.manchester.ac.uk) is one of the largest faculties of clinical and health sciences in Europe, with a research income of over £37 million.

The School of Medicine (www.medicine.manchester.ac.uk) is the largest of the Faculty’s five Schools, with 1300 staff, almost 2000 undergraduates and a £32M research income. The School encompasses five teaching hospitals, and is closely linked to a range of general hospitals and community practices across the North West of England.

How To Build Muscle While You Age

Experts at The University of Nottingham are to investigate the effect of nutrients on muscle maintenance in the hope of determining better ways of keeping up our strength as we get old.

The researchers, based at the School of Graduate Entry Medicine and Health in Derby, want to know what sort of exercise we can take and what food we should eat to slow down the natural loss of skeletal muscle with ageing.

The team from the Department of Clinical Physiology, which has over 20 years experience in carrying out this type of metabolic study, need to recruit 16 healthy male volunteers in two specific age groups to help in it’s research.

Skeletal muscles make up about half of our body weight and are responsible for controlling movement and maintaining posture. However, at around 50 years of age our muscles begin to waste at approximately 0.5 per cent to one per cent a year. It means that an 80 year old may only have 70 per cent of the muscle of a 50 year old.

Since the strength of skeletal muscle is proportional to muscle size, such wasting makes it harder to carry out daily activities requiring strength, such as climbing stairs and leads to a loss of independence and an increased risk of falls and fractures.

In order for skeletal muscles to maintain their size, the large reservoirs of muscle protein require constant replenishment in the way of amino acids from protein contained within the food we eat. In fact, amino acids from our food act not only as the building blocks of muscle proteins but also actually ‘tell’ our muscle cells to build proteins.

Recent research from the clinical physiology team has shown that the cause of muscle wasting with ageing appears to be an attenuation of muscle building in response to protein feeding. In other words, as we age we lose the ability to covert the protein in the food we eat in to muscle tissue. The proposed research will investigate the mechanisms responsible for this deficit.

Dr Philip Atherton, who is currently recruiting volunteers, said: “I am really excited to be involved in this project because if we can determine ways to better maintain muscle mass as we age it will greatly benefit us all.”

The researchers are looking for 16 healthy, non-smoking, male volunteers aged 18 to 25 and 65 to 75.

Initially, the volunteers will undergo a health screening and then on a different day, under the supervision of a doctor, will be infused with an amino acid mixture to simulate feeding along with a ‘tagged’ amino acid that allows them to assess muscle building. To make these measures, blood samples will be taken from the arm and muscle biopsies from the thigh muscle under local anaesthesia. Volunteers will receive an honorarium to cover their expenses.

———————————–
Article adapted by MD Sports from original press release.
———————————–

Contact: Lindsay Brooke
University of Nottingham

 

The study will take place at The University of Nottingham’s Medical School which based at the City Hospital in Derby.

Research Finds New Muscle Building Protein

Investigators in The Research Institute at Nationwide Children’s Hospital have identified the role of a protein that could potentially lead to new clinical treatments to combat musculoskeletal diseases, including Duchenne muscular dystrophy (DMD).

Results of these studies appear in the March 11, 2008 issue of the Proceedings of the National Academy of Sciences.

These studies, led by Brian Kaspar, PhD, a principal investigator in the Center for Gene Therapy at The Research Institute and an assistant professor of Pediatrics at The Ohio State University, focus on a protein called follistatin (FS). Using a single injection, gene-delivery strategy involving FS, investigators treated the hind leg muscles of mice. Results showed increased muscle size and strength, quadruple that of mice treated with proteins other than FS. The muscle enhancements were shown to be well-tolerated for more than two years.

According to Dr. Kaspar, increased muscle mass and strength were also evident when this strategy was tested using a model of DMD. Apart from the injected hind leg muscles, strengthening effects were also shown in the triceps. In addition, fibrosis, abnormal formation of scar tissue and a hallmark of muscular dystrophy, was decreased in FS-treated animals.

“We believe this new FS strategy may be more powerful than other strategies due to its additional effects, including its ability to reduce inflammation,” said Dr. Kaspar.

The strategy showed no negative effects on the heart or reproductive ability of either males or females. The results were also replicated in older animals, suggesting that this strategy could be useful in developing clinical treatments for older DMD patients.

“This research provides evidence of multiple potential treatment applications for muscle diseases including, but not limited to, muscular dystrophy,” said Jerry Mendell, MD, director of the Center for Gene Therapy at The Research Institute, a co-author on the study, and professor of Pediatrics in Neurology and Pathology at The Ohio State University. “These results offer promise for treatment of potentially any muscle-wasting disease, including muscle weakness due to other illnesses, aging, and inflammatory diseases such as polymyositis. Our next step is to pursue clinical trials.”

The Research Institute at Nationwide Children’s Hospital has a patent pending on the FS technique due to the major role it may play for muscular dystrophy treatment and other muscle-wasting diseases.

———————————–
Article adapted by MD Sports from original press release.
———————————–

Contact: Pam Barber/Mary Ellen Fiorino
Nationwide Children’s Hospital

Androgens Increase Strength Not Muscle Size

USC study finds combining resistance training and androgens gives more muscular bang for the buck

PHILADELPHIA (June 19, 2003)-Men who take supplemental androgens-the male hormone testosterone or similar medications-increase their strength by adding muscle mass, but androgens alone do not pack more might into the muscles, according to studies presented today by University of Southern California researchers.

Treatment with androgens increases lean body mass-which encompasses everything in the body but bone and fat-and strength increases proportionately with the amount of muscle added, says E. Todd Schroeder, Ph.D., postdoctoral fellow in the Department of Medicine at the Keck School of Medicine of USC and adjunct assistant professor in the USC Department of Biokinesiology and Physical Therapy. Schroeder presented his findings at the Endocrine Society’s 85th Annual Meeting.

However, when men use androgen therapy combined with resistance training, such as weightlifting, their gains in strength may far outpace the amount of muscle that can be added with androgens alone. Each muscle cell packs a bigger punch, a concept known as improved muscle quality.

“The results of androgen therapy alone on muscle and strength are not necessarily bad, but they are not optimal,” Schroeder says. “The men did improve their strength, but it was proportional to the muscle mass they added.”

The findings wield health implications beyond the stereotypes of muscle-bound bodybuilders. Schroeder and his colleagues are studying the usefulness of androgens and exercise in helping maintain muscle strength, muscle power and physical function among seniors, for example. They also have studied androgen therapy’s effectiveness in battling wasting among HIV-positive patients.

In their recent study, Schroeder and USC colleagues Michael Terk, M.D., and Fred R. Sattler, M.D., looked at both young men and seniors. They followed two groups: 33 seniors ranging from their mid-60s to late 70s, and 23 HIV-positive men ranging from their early 30s to late 40s.

The younger men were randomly assigned to get 600 milligrams (mg) each week of nandrolone alone or in combination with resistance training. The older men were randomly assigned to receive 20 mg a day of oxandrolone or a placebo. These pharmacologic androgen doses were given over 12 weeks.

Researchers determined maximal strength-the most weight a participant could safely lift or push-using leg press, leg extension and leg flexion machines.

The researchers also measured the cross-sectional area of participants’ thighs and the lean body mass of their lower extremities by magnetic resonance imaging, or MRI. They then determined the strength that participants exerted for each unit of muscle (muscle quality) and how muscle quality changed over time.

Androgens alone increased lean body mass and maximum strength in both groups of men, but “gains were modest,” Schroeder says, and muscle quality did not change, since the muscle size and strength both increased proportionately. However, among those using nandrolone and undergoing resistance training, muscle quality improved significantly: Gains in strength were much greater than the gains that could occur from muscle-mass increase alone.

“It is clear from our studies and others that resistance training is critical for increasing muscle quality, but the effects can probably be augmented with androgens,” Schroeder says. “In addition, not everyone can do resistance training, and a short course of androgens can help get people stronger and more functional.”

Finally, results provide researchers insight into how to better design future studies to test strategies to best preserve and even improve muscle strength and physical function among seniors. Similar studies will be important for other types of patients who experience muscle loss and frailty, such as those with cancer, chronic lung disease, chronic renal failure and other conditions.

———————————–
Article adapted by MD Sports from original press release.
———————————–

Contact: Jon Weiner
University of Southern California

Grants by the National Institute of Diabetes & Digestive & Kidney Diseases and the National Center for Research Resources (General Clinical Research Center) supported the research. Bio Technology General Corp., which makes Oxandrin (oxandrolone), also supported part of the research.

Edward T. Schroeder, Michael Terk and Fred R. Sattler, “Pharmacological Doses of Androgen Do Not Improve Muscle Quality in Young or Older Men: Results from Two Studies,” Endocrine Society’s 85th Annual Meeting, poster P3-212, presentation 11 a.m., June 21. Findings released at news conference 1:30 p.m., June 19.

Creatine Supplement May Help People With Muscular Dystrophies

Creatine, a popular nutritional supplement used by weightlifters and sprinters to improve athletic performance, could lend muscle strength to people with muscular dystrophies.

Muscle strength increased by an average of 8.5 percent among patients taking creatine, compared to those who did not use the supplement, according to a recent review of studies. Creatine users also gained an average of 1.4 pounds more lean body mass than nonusers.

The evidence from the studies “shows that short- and medium-term creatine treatment improves muscle strength in people with muscular dystrophies and is well-tolerated,” said lead reviewer Dr. Rudolf Kley of Ruhr University Bochum in Germany.

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Creatine is found naturally in the body, where it helps supply energy to muscle cells. Athletes looking for short bursts of intense strength have used creatine in powders or pills for decades, but the supplement became more popular after the 1992 Barcelona Olympics, when sprinters, rowers and cyclists went public with their creatine regimens.

Although creatine has been widely studied as a performance enhancer, it’s still not clear if the supplement makes a difference, according to Roger Fielding, Ph.D., of Tufts University, who has also recently written a review of creatine treatments for neuromuscular diseases.

People with muscular dystrophies can have lower-than-normal levels of creatine, along with increasing muscle weakness as their disease progresses. Since some studies suggest that creatine improves muscle performance in healthy people, many researchers have reasoned that it might be helpful in treating muscle disease.

The Cochrane researchers reviewed 12 studies that included 266 people with different types of muscular dystrophy. People in the studies who took creatine supplements used them for three weeks to six months.

In muscular dystrophies, the proteins that make up the muscles themselves are either missing or damaged. In a related group of disorders called metabolic myopathies, the chemicals that help muscles operate go awry.

Although creatine seemed to help many patients with muscular dystrophies, those with metabolic myopathies gained no more muscle strength or lean body mass than patients who did not use the supplement.

The reason for the contrasting results — creatine’s “fairly consistent” effects in muscular dystrophy and lack of effectiveness in metabolic diseases — is “not entirely clear,” Kley said, calling for more research on treatment for metabolic disorders.

The review was supported by the Neuromuscular Center Ruhrgebiet/Kliniken Bergmannsheil, at Ruhr-University Bochum and the Hamilton Health Sciences Corporation, in Canada. Kley and colleagues have each participated in trials of creatine treatment for muscle disorders, although none of the studies was sponsored by a maker of creatine.

—————————-
Article adapted by MD Sports from original press release.
—————————-

FOR MORE INFORMATION
Health Behavior News Service: hbns-editor@cfah.org

Kley RA, Vorgerd M, Tarnopolsky MA. Creatine for treating muscle disorders. Cochrane Database of Systematic Reviews 2007, Issue 1.

The Cochrane Collaboration is an international nonprofit, independent organization that produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. Visit http://www.cochrane.org for more information.

Creatine enhances strength in older adults

Lower muscle mass and an increase in body fat are common consequences of growing older.

While exercise is a proven way to prevent the loss of muscle mass, a new study led by McMaster researcher Dr. Mark Tarnopolsky shows that taking a combination of creatine monohydrate (CrM) and conjugated linoleic acid (CLA) in addition to resistance exercise training provides even greater benefits.

The study to be published on Oct. 3 in PLoS One, an international, peer-reviewed online journal of the Public Library of Science, involved 19 men and 20 women who were 65 years or older and took part in a six-month program of regular resistance exercise training.

In the randomized double blind trial, some of the participants were given a daily supplement of creatine (a naturally produced compound that supplies energy to muscles) and linoleic acid (a naturally occurring fatty acid), while others were given a placebo. All participants took part in the same exercise program.

The exercise training resulted in improvements of functional ability and strength in all participants, but those taking the CrM and CLA showed even greater gains in muscle endurance, an increase in fat-free mass and a decrease in the percentage of body fat.

“This data confirms that supervised resistance exercise training is safe and effective for increasing strength and function in older adults and that a combination of CrM and CLA can enhance some of the beneficial effects of training over a six month period,” said Tarnopolsky, a professor of pediatrics and medicine.

This study provides functional outcomes that build on an earlier mechanistic study co-led by Tarnopolsky and Dr. S. Melov at the Buck Institute of Age Research, published in PLoS One this year, which provided evidence that six months of resistance exercise reversed some of the muscle gene expression abnormalities associated with the aging process.
—————————-
Article adapted by MD Sports Weblog from original press release.
—————————-

Contact: Veronica McGuire
McMaster University

“MIGHTY MOUSE” Gene Increases Muscle Mass in Humans

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.)

—————————-
Article adapted by MD Sports Weblog from original press release.
—————————-

 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.