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— Subtle defects in the processing of a single protein that provides structural integrity to muscle cells can lead to several devastating forms of muscular dystrophy, according to studies by Howard Hughes Medical Institute researchers and their colleagues at the University of Iowa. The scientists reported in two papers published in the July 25, 2002, issue of the journal Nature that defects in enzymes responsible for the processing of the structural protein dystroglycan are the underlying cause of several rare forms of muscular dystrophy that affect muscles and cause additional developmental brain abnormalities including mental retardation. The new findings will immediately help doctors in providing accurate diagnosis and appropriate genetic counseling to patients and their families. In the longer term, knowing the underlying cause of the muscular dystrophies will help researchers tailor their interventions, according to Howard Hughes Medical Institute investigator Kevin Campbell . The disorder also disrupts an important component of learning and memory, so Campbell is hopeful that his team’s studies will improve understanding of possible links between muscle physiology and neurobiology. ©2002 Howard Hughes Medical Institute
By DENISE GRADY Researchers in the Netherlands have developed a drug that may eventually be used to treat children with a severe and fatal type of muscular dystrophy. Times Health Guide: Duchenne’s Muscular DystrophyIn its first test in humans, a safety study in just four boys, the drug enabled patients to produce an essential muscle protein that is missing in Duchenne’s muscular dystrophy, a genetic disease. Not enough of the protein was produced to help the boys, but the presence of any at all was considered “proof of concept,” meaning that the approach has the potential to work and is worth pursuing. The experimental drug, called an “antisense” compound, works by canceling out the effects of certain genetic mutations. These types of drugs are being studied to treat cancer, heart disease, infections and other illnesses. “I don’t think you could ask for a better result from a preliminary study like this,” said Sharon Hesterlee, the vice president for translational research at the Muscular Dystrophy Association, which was not involved in the study but helped pay for an earlier phase of the work. Though promising, the research still has a long way to go. The four boys, ages 10 to 13, each received just one injection into a leg muscle. There were no adverse effects. But larger and longer trials with much higher doses, given systemically so that the drug reaches all muscles, are needed to test both safety and efficacy. If the treatment works, it will have to be given regularly, for life. Copyright 2007 The New York Times Company
Roxanne Khamsi An experimental cancer drug has slowed muscular dystrophy in mice with the disease, raising hopes that a simple pill could one day treat the fatal condition in humans. “The results the researchers are reporting are very dramatic and impressive,” says Jeff Chamberlain at the University of Washington School of Medicine in Seattle, US. The researchers caution that the results are preliminary, but say that the approach might offer advantages over other medicines for muscular dystrophy currently in clinical trials. There are many forms of the muscle-wasting disease, but no cure for any of them. The most common form of the illness among children, known as Duchenne muscular dystrophy, involves a mutation for a muscle protein known as dystrophin. Without functioning copies of this protein, muscles weaken, leading to breathing problems and, ultimately, death in the victims' teens or early twenties. Pier Puri at the Burnham Institute in La Jolla, California and colleagues tried to boost muscle function in mice carrying a mutation in the dystrophin gene, by treating the animals with a cancer drug called trichostatin A (TSA). © Copyright Reed Business Information Ltd.
Linda Geddes, reporter A gene therapy that appears to bulk up muscle mass and strength in monkeys - reported today in Science Translational Medicine - will undoubtedly raise fresh concerns about the potential for gene doping in sport. We already know that some athletes use drugs like erythropoietin to increase the amount of oxygen their blood delivers, and steroids to bulk up muscle mass. The big advantage with gene doping is that it should be harder to detect. That's because it's difficult to test for a protein that the body already produces, especially when its levels naturally vary between individuals - which might explain why some people are inherently better at sports than others. In the new study, Janaiah Kota and colleagues at Nationwide Children's Hospital in Columbus, Ohio, used gene therapy to add extra copies of the follistatin gene into the leg muscles of monkeys. Follistatin has been previously shown in mice to block myostatin, a protein that decreases muscle mass, resulting in bulked up "mighty mice". Monkeys injected with the gene also seemed to bulk up, and when Kota's team analyzed their leg muscles with a device that measures force, they found that the muscles injected with the follistatin gene were also stronger than normal muscles. They hope the approach could eventually be used to treat the severe muscle weakness associated with neuromuscular disorders like muscular dystrophy and multiple sclerosis. © Copyright Reed Business Information Ltd.
Fenella Saunders The simple act of bending a knee requires the coordination of more strings than a symphony orchestra. Each muscle cell is made up of many tiny filaments of proteins. When a muscle contracts, these fibers change shape and slide past one another, creating vibrations. "It's like plucking a string, and the sound can tell you about the elastic properties of the muscle," says Karim Sabra, a mechanical engineer at the Georgia Institute of Technology. Sabra is measuring the noise from healthy muscles in the hope that this baseline information could be used in the future to help diagnose muscular diseases or injuries. It's possible to hear muscular noise for yourself. If you place your thumbs gently over your ear openings so they completely cover your ear canals, then with your elbows raised tighten your hands into fists, you will hear a sound that resembles distant rolling thunder, which becomes louder the tighter the fist is made. This phenomenon was first described in the late 1600s. Leg muscle sounds were first observed in the 1800s. During contraction, the overall volume of a muscle fiber stays the same. So in order to shorten, the fiber has to expand in width. The muscles become harder during this process. "Sound travels faster through stiffer muscles, and slower through softer ones," explains Sabra. © Sigma Xi, The Scientific Research Society
By Steve Mitchell The recent breakthrough of skin cells reprogrammed to behave like embryonic stem cells has stolen the spotlight (ScienceNOW, 6 December), but adult stem cells are proving that they have advantages of their own. In the 13 December issue of Cell Stem Cell, researchers report using stem cells from patients afflicted with a form of muscular dystrophy to correct the disorder in mice. The results suggest that this strategy could one day treat muscular dystrophy in humans as well as other genetic disorders. Duchenne muscular dystrophy, which predominantly strikes boys, is caused by a mutation in the gene for a protein called dystrophin that is essential for proper muscle function. The condition leads to muscle degeneration, and patients usually die in their 30s. A particular type of stem cell found in muscle can give rise to new muscle tissue, so a team led by geneticist Luis Garcia of Généthon, a nonprofit biotechnology firm in Évry, France, investigated whether these cells could be used to reverse the dystrophin problems. The researchers first obtained the stem cells from patients via a muscle biopsy. Next, they used a virus to insert a gene into the cells that corrects the mutation in the dystrophin gene. The researchers then injected the modified stem cells into arteries of the legs of mice with muscular dystrophy. In just 3 weeks, muscles in the foot, shin, and thigh began expressing human dystrophin protein, indicating that the stem cells had given rise to muscle cells that had taken up residence in the muscles of the mice. © 2007 American Association for the Advancement of Science
Related chapters from BP7e: Chapter 11: Motor Control and Plasticity; Chapter 7: Life-Span Development of the Brain and Behavior
Related chapters from MM:Chapter 5: The Sensorimotor System; Chapter 13: Memory, Learning, and Development
Link ID: 11085 - Posted: 06.24.2010
By Howard Schneider The People Who Know What's Good For Us have made life progressively difficult, moving from general recommendations such as "maintain ideal weight" to detailed orders for 60 to 90 minutes of exercise every day. You can now add weightlifting to the creeping set of obligations. It's not explicit in the government's overall guidelines, but the more detailed suggestions from agencies such as the Centers for Disease Control and Prevention recommend a couple of rounds of resistance training each week. (And, yes, Vicky, that includes you cardio junkies out there because aaaallllll thaaaaatttt time on the treadmill won't guarantee that you can sit up straight when 27 becomes 77.) This won't make a lot of us happy. The basic exercise recommendations are pretty easy to cope with: Take a walk. Ride a bike. Lather, rinse, repeat. Weightlifting, on the other hand, conjures the threat of being stuck next to some grunting mesomorph who will one day be governor. The chance of injury is greater. The advice gets confusing and may include a lecture about how, if you don't disrupt the Z lines between your sarcomeres, it's a waste of time. It's manageable, however, if you understand some basics. The reason there is so much varying advice -- over what exercises to do, how frequently and how intensely -- is that this is an enterprise that should be tailored to your goals and your body. Cardio focuses on training just one muscle, the heart. There are more than 600 others that need attention. © 2007 The Washington Post Company
Debora Mackenzie STEM cells have helped dogs with muscular dystrophy to walk again. Doctors hope a similar approach in humans could lead to more complete improvement than the other leading contender for a cure - an RNA-blocking drug now in clinical trials. Duchenne muscular dystrophy (DMD) strikes about one in 35,000 children, almost always boys, and is usually fatal by the age of 30. It is caused by mutations in the gene for the muscle protein dystrophin. Without it, muscle contractions shear and kill muscle cells, and victims become progressively weaker, often dying when their breathing muscles fail. Giulio Cossu and colleagues at the San Raffaele Scientific Institute in Milan, Italy, had found previously that adult stem cells called mesangioblasts colonise muscle and restore dystrophin production in mice engineered to lack the gene. But the therapeutic effect could not be tested, because these mice do not develop MD. Dogs do. So Cossu's team took mesangioblasts from golden retrievers with a mutation in the dystrophin gene that causes a disease similar to DMD. They used gene therapy to give the cells a normal version of the gene, before reinjecting them into the dogs' leg arteries. They also transplanted mesangioblasts from healthy dogs into dogs with MD, and gave drugs to suppress immune rejection (Nature, DOI: 10.1038/nature05282). © Copyright Reed Business Information Ltd
When 8 year-old Andrew Kilbarger of Lancaster, Ohio received three injections in his right arm, he became one of six boys participating in the first U.S. gene therapy trial for muscular dystrophy. Andrew has Duchenne Muscular Dystrophy (DMD). DMD patients lack the gene that controls production of a protein called dystrophin, which helps keep muscle cells intact. Patients with DMD usually die by the age of 25, often because of the failure of the heart and breathing muscles. The start of any new gene therapy trial is an exciting time. But for the Muscular Dystrophy Association (which funded the trial), and the participants and doctors involved at Columbus Children's Hospital, this is a particularly exciting event because for this disease, it has been a long, hard road. Researchers discovered the gene for dystrophin 20 years ago but since it is one of the largest genes known, it was too big to work with. In 2000, geneticist Xiao Xiao found a way to miniaturize the gene. His team at the University of Pittsburgh tested the "mini-dystrophin" gene in a strain of mice with muscular dystrophy. The improvement seen in the muscle tissue of the mice was dramatic, and led to the human trial that just began. "The limitation of that is the gene vehicle will not be widespread. It will… be localized around the injection site. However, diseases like muscular dystrophy affect almost every skeletal muscle cell," he says." So you cannot, in theory, inject the genes into every muscle cell directly. So we have to figure out a novel or innovative way to deliver or disseminate [the gene]." © ScienCentral, 2000-2006.
Rowan Hooper THANKS to research on "mighty mice", the lives of people suffering from muscle-wasting diseases such as muscular dystrophy could be transformed. Two treatments that block a protein called myostatin, which slows muscle growth, are now in the pipeline. The first approach, announced this week, aims to use a drug to mop up myostatin. Meanwhile a second method, which is already in clinical trials in people with muscular dystrophy, uses antibodies to disable the protein. In 1997, researchers led by Se-Jin Lee of Johns Hopkins University School of Medicine in Baltimore, Maryland, engineered mice in which the gene for myostatin had been "knocked out". The animals grew muscles twice as big as normal. A defect in the myostatin gene was what caused a German toddler, whose story was widely publicised last year, to develop prodigious muscles. Now Lee has produced a soluble molecule called activin type IIB receptor (ACVR2B) that binds to myostatin in normal mice, causing their muscles to bulk up. He hopes ACVR2B can be used to treat conditions such as Duchenne muscular dystrophy, a genetic disease that affects 1 in 3000 boys. Their muscles waste away because of a defect in the gene for the protein dystrophin, which is important in organising muscle structure. © Copyright Reed Business Information Ltd
Yawn. Stretch. Grumble. Retch. No matter. All muscle motion starts with a nerve signal: Move, muscle, now! You know the drill: Brain activates nerve, nerve stimulates muscle cell, and something happens. Things are different in the fruitfly. This mainstay of the compost heap and the biology lab beats its wings 200 times a second. Even Why Filers can do the math: 200 contractions of the muscles that lift the wings, and another 200 in the muscles that pull them back down. All in one second. That's a problem because it's much faster than nerves can trigger muscles, says Thomas Irving, associate professor of biology at the Illinois Institute of Technology, and director of the Biophysics Collaborative Access Team . "Human muscle needs a nerve impulse, but the insect has got to do it 200 times a second," and so the triggering "has to be done at the molecular level." To explore the molecular level, Irving and colleagues, including fruit-fly flight expert Michael Dickinson of Caltech, triggered some muscular activity of their own. They glued the head of a living fruitfly to a wire and placed it in a bath of X-rays at the Advanced Photon Source at Argonne National Laboratory in Illinois. They put on a light show to force the fly to adopt a steady wingbeat, and aimed brief surges of tightly focused X-rays at the critter's wing muscles. You can read their results in this week's Nature. ©2005, University of Wisconsin, Board of Regents.
Peter Weiss In a Los Angeles laboratory, researchers have let loose scores of what amount to living micromachines. Dwarfed by a comma, each tiny device consists of an arch of gold coated along its inner surface with a sheath of cardiac muscle grown from rat cells. With each of the muscle bundles' automatic cycles of contraction and relaxation, the device takes a step. Viewed under a microscope, "they move very fast," says bioengineer Jianzhong Xi of the University of California, Los Angeles (UCLA). "The first time I saw that, it was kind of scary." Xi and his UCLA colleagues Jacob J. Schmidt and Carlo D. Montemagno describe their musclebots in the February Nature Materials. Microcontraptions of this sort may someday make pinpoint deliveries of drugs to cells or shuttle minuscule components during the manufacture of other itsy machines or structures, Xi says. Variations on the same design could lead to muscle-driven power supplies for microdevices or laboratory test beds for studying properties of muscle tissue. Because the musclebot is both minuscule and designed to operate in body fluids, "this is the Fantastic Voyage kind of thing" that might someday roam the bloodstream and carry out on-the-spot surgery or disease treatments, comments physicist James Castracane of the State University of New York in Albany. Copyright ©2005 Science Service.
John Travis Find the kid a sports agent. Researchers studying an unusually muscular tot have found that he has gene mutations similar to ones that produce abnormally brawny cattle and mice. Less-severe variations in the same gene may underlie the success of some athletes, the scientists speculate. The boy's mutations disrupt both copies of the gene encoding a muscle protein called myostatin. Previous studies of the gene in animals had suggested that myostatin restrains muscle growth during development and adult life. But scientists didn't know whether the protein serves the same function in people. The boy's powerhouse physique "says pretty definitively that myostatin plays the same role in humans that it does in mice and cattle," concludes Se-Jin Lee of Johns Hopkins Medical Institutions in Baltimore. If so, he adds, then drugs to block myostatin might have some benefits in people with muscle-wasting diseases. Lee is a member of the international group of investigators who have studied the boy since 1999 and now report their results in the June 24 New England Journal of Medicine (NEJM). Copyright ©2004 Science Service.
BOSTON - A genetic mutation in "mighty mice" is also found in a German boy with unusually large muscles, scientist say. The four-year-old's muscles are roughly twice as large as other children his age. Researchers found he has an inherited mutation in the myostatin gene, boosting muscle growth and reducing fat. "This is the first evidence that myostatin regulates muscle mass in people as it does in other animals," said Dr. Se-Jin Lee, a professor of molecular biology and genetics at Johns Hopkins University in Baltimore, and a co-author of the study. Naturally bulky cattle such as Belgian Blues also lack myostatin, the researchers have found. Lee's team wants to explore if interfering with myostatin can slow down muscle loss in muscle wasting diseases such as Duchenne muscular dystrophy. About 850 males in Canada have the disease. Seven years ago, Lee's team created mice that are twice as brawny as normal by blocking the mysotatin gene. Both Lee and his university would share in royalties if the research results in any commercial therapies. Copyright © CBC 2004
EDMONTON - By implanting computer chips in the body, researchers in Alberta hope to make paralysed limbs work again. Scientists at the University of Alberta developed a device to stimulate nerves to take a step. The device helped Edgar Jackson of Calgary regain the ability to walk. Five years ago, a motorcycle accident left him a quadriplegic. A video shows the difference the device made. Jackson went from struggling to put one foot in front of the other to walking with ease. Here's how it works. A sensor attached to Jackson's leg recognizes when his foot is being lifted. Then an electric shock is triggered to stimulate the nerve, moving the foot into position to take a normal step. Copyright © CBC 2004
A common question flowing across holiday tables trimmed with turkey this week may be "white meat or dark?" Now scientists have identified the genetic switch that governs the formation of the two types during development. White and dark meat differ in appearance because each is made up of a distinct type of muscle fiber. Dark meat comprises so-called slow twitch muscle fibers, which are specialized for extended exertion, whereas white meat is made up of fast twitch fibers that fuel short, intense bursts of energy. That much has been known for some time. The genetic mechanism underlying the specification of one muscle type versus the other was unclear, however. Philip Ingham of the University of Sheffield and his colleagues studied muscle cells of developing zebrafish and found that a gene dubbed u-boot (ubo ) plays a key role in determining what type of muscle develops by controlling the transcription factor protein known as Blimp-1. © 1996-2003 Scientific American, Inc.
Detergent delivers genetic medicine to mice with muscular dystrophy. HELEN R. PILCHER A mouse study raises hopes that injections of the DNA-like molecule RNA might one day help to treat the muscle-wasting disease Duchenne muscular dystrophy. For the first time in a live animal, RNA therapy has produced improvements that last for up to three months1. Duchenne muscular dystrophy is an inherited disease that affects 1 in 3,500 children, mainly boys. Sufferers inherit a fault in the gene encoding the protein dystrophin, causing most to die in early adulthood. The new approach effectively corrects the flawed gene. It targets RNA - the intermediate between DNA and protein. Snippets of RNA, injected directly into the muscle, help edit out damaged pieces of host RNA. Muscle cells can then produce the missing dystrophin protein. © Nature News Service / Macmillan Magazines Ltd 2003
-- A protein that plays a role in muscular dystrophies also may be involved in peripheral neuropathy - disorders of the nerves that carry messages between the brain and the rest of the body. The findings, by University of Iowa researchers and colleagues, may shed light on the causes and mechanisms of human peripheral neuropathies, which cause pain, numbness and muscle wasting. Peripheral neuropathies can be acquired as a result of diseases including diabetes and Hansen's disease (leprosy) or can be inherited. Some congenital peripheral neuropathies (those present at birth) can cause limb deformities. The UI study may suggest new treatment strategies for these conditions. In the peripheral nervous system, dystroglycan is found in Schwann cells, which wrap themselves around peripheral axons (nerve fibers) and protect them by producing a myelin sheath. The sheath allows nerve impulses to move faster and more efficiently along the nerves. If nerve fibers are the body's electrical wiring, then the myelin sheath represents the insulation. Copyright © 1992-2003 Bio Online, Inc.
A protein defective in two types of muscular dystrophy also appears to be important in repairing damaged muscle, according to Howard Hughes Medical Institute researchers at the University of Iowa College of Medicine. The discovery reveals the first known component of the machinery that repairs the damaged membrane in a muscle fiber. Further studies of this and related proteins could lead to a better understanding of disorders that affect cardiac and skeletal muscles. Howard Hughes Medical Institute investigator Kevin Campbell and Dimple Bansal led the research group that published its findings in the May 8, 2003, issue of the journal Nature. Campbell and his colleagues reported that their studies in mice showed that a mutant form of the muscle protein dysferlin prevents normal muscle repair in limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi Myopathy (MM). Campbell and his colleagues at the University of Iowa College of Medicine collaborated with Paul McNeil and his laboratory at The Medical College of Georgia. ©2003 Howard Hughes Medical Institute
HOUSTON - A newly identified gene, atrogin-1, is involved in muscle loss associated with cancer, diabetes, fasting and kidney disease as well as in the atrophy occurring with disuse, inactivity, and nerve or spinal injury. This discovery, funded by the National Space Biomedical Research Institute (NSBRI) and the Muscular Dystrophy Association, increases the understanding of how muscles atrophy and may lead to development of new treatments for muscle wasting on Earth and in space. "Through a study of rat muscles, we determined that atrogin-1 is found only in muscle," said Dr. Alfred Goldberg, professor of cell biology at Harvard Medical School and associate leader of NSBRI's team of scientists focusing on muscle loss in space. "In normal muscles, the amount is low; however, there is a dramatic increase in the production of the atrogin-1 protein in conditions where muscles lose size and strength." Copyright © 2000-2002 National Space Biomedical Research Institute