Posts Tagged ‘how to build muscle’

“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.

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Article adapted by MD Sports from original press release.
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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.

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.

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.

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Article adapted by MD Sports from original press release.
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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.