Research Updates November-December 2004

Article Highlights:

Research news as of October 2004

by Quest Staff on November 1, 2004 - 12:22pm

In this article, the latest research news about: stem cells, Duchenne MD, distal MD, FSH muscular dystrophy, guidelines for DMD care

Stem cells with muscle potential found

Yvan Torrente at the University of Milan in Italy, and colleagues in Italy and France, have discovered a way to identify stem cells circulating in human blood that have the capacity to become muscle cells.

Giulio Cossu of the Stem Cell Research Institute of the San Raffaele Hospital in Milan is MDA-supported for closely related work and was part of this research team.

The findings show that cells circulating in human blood that display a protein called AC133 on their surfaces can become muscle cells when exposed to certain substances in the laboratory or when injected directly into a muscle or an artery in mice.

When the researchers injected the human-derived, AC133-displaying cells into mice with a disease resembling Duchenne muscular dystrophy (DMD), at least some of the cells became muscle cells. (The mice also had an immune-system defect that allowed them to accept the human cells.)

Some AC133 cells became satellite cells, a type of cell present around muscle fibers that can move into the fiber and become muscle when repairs are needed. Others appeared to become muscle cells.

“As these cells can be isolated from the blood, manipulated in vitro [in lab dishes], and delivered through the circulation, they represent a possible tool for future cell therapy applications in DMD disease or other muscular dystrophies,” the researchers note in their paper, which is published in the July issue of the Journal of Clinical Investigation.

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Enzyme key to steroid success in Duchenne MD

Bernard Jasmin
Bernard Jasmin
Lynn Megeney
Lynn Megeney

Corticosteroid drugs such as prednisone and deflazacort are often prescribed to slow the loss of muscle strength in Duchenne muscular dystrophy (DMD) and other neuromuscular diseases.

Both apparently lead to increased production of the protein utrophin, which is similar to dystrophin — the protein missing in DMD — and can to some extent compensate for its absence.

Now, MDA grantees Lynn Megeney at Ottawa Health Research Institute in Ontario and Bernard Jasmin, in the Department of Cellular and Molecular Medicine at the University of Ottawa, and colleagues, have unraveled the precise biochemical pathway that leads to this helpful utrophin increase (upregulation).

The new findings, published online Sept. 29 in the FASEB (Federation of American Societies for Experimental Biology) Journal, tie together previous research showing that the enzyme calcineurin is needed for dystrophin-deficient cells to regenerate and that corticosteroids increase utrophin production in such cells.

The researchers have now shown that increases in calcineurin allow DMD-affected cells to go around a biochemical pathway called JNK1, which would ordinarily lead to their death, and that increasing utrophin production is among the chief benefits of evading this pathway.

“Our observations now clarify the mechanism by which corticosteroids achieve their effects,” Megeney says. “This study also confirms the notion that dystrophy pathology originates in part from elevated JNK1 activity and that pharmacologic correction or limitation of this pathway by upregulating calcineurin is a valid approach to treating this disease.”

Megeney notes that the side effects of corticosteroid medications, such as weight gain, cataracts, bone loss and psychological problems, have posed significant obstacles to their use. With new information on how these powerful chemicals actually help in DMD, better, more specifically targeted drugs could be developed, he says.

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Fourth gene found for distal muscular dystrophy

Peter Hedera
Peter Hedera
Peter Hedera
Nigel Laing

MDA grantees Peter Hedera, a neurologist at Vanderbilt University in Nashville, Tenn., and Nigel Laing, a molecular biologist at the University of Western Australia in Nedlands, were part of a team that identified a fourth gene that, when flawed, leads to distal muscular dystrophy (DD). Three other genes have previously been identified for this type of MD.

The new DD gene, called MYH7, carries instructions for a protein known as a myosin heavy chain. It’s needed in heart and skeletal muscle cells, and abnormalities in it have previously been found to cause cardiomyopathy (cardiac muscle disease) and myosin storage myopathy, a muscle disease.

The new link between MYH7 and DD was published online in the American Journal of Human Genetics on Aug. 20.

DD, which weakens the muscles of the forearms, hands, lower legs and feet, can result from flaws in at least seven (four known and at least three unidentified) genes for proteins affecting muscles.

The MYH-7 form, which can cause symptoms as early as age 4, is known as Laing early-onset distal MD (or distal myopathy). Nigel Laing and colleagues narrowed the location of the disease-causing gene flaw to chromosome 14 in 1995. People with Laing DD usually don’t have cardiomyopathy.

The precise identification of disease-causing gene flaws (mutations) generally leads to improved diagnostic procedures right away, and to improved treatment in the long run.

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More good news about IGF1 in Duchenne MD

MDA grantees Paul Gregorevic at the University of Washington in Seattle and Gordon Lynch at the University of Melbourne in Victoria, Australia, with David Plant (Melbourne), recently published their observations of the benefits of insulin-like growth factor 1 (IGF1) in lessening the effects of Duchenne muscular dystrophy (DMD).

In the September issue of Muscle & Nerve, the researchers describe how IGF1, delivered to DMD-affected mice via a pump implanted under the skin, allowed the two leg muscles tested to resist fatigue after repeated contractions.

Lynch’s previous work with this protein, which is produced in the body but can also be administered as a drug, has shown that delivering it by pump can improve the abilities of the diaphragm muscles of DMD-affected mice to resist fatigue and generate force. (See “Research Updates,” Quest, December 2002 .)

A trial of the drug SomatoKine, which is a combination of IGF1 and another protein that may improve its action and reduce side effects, will soon be under way in a small group of people with myotonic muscular dystrophy. That trial, at the University of Rochester (N.Y.) Medical Center, is slated to begin by the end of the year.

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Prediction of FSHD severity especially tricky

Genetic testing for neuromuscular disease has come a long way in the past decade, but even now, there are pitfalls when it comes to predicting the likelihood of passing on a genetic disorder to a child or predicting the severity of the disorder.

MDA grantee Silvere van der Maarel at Leiden University in the Netherlands, and colleagues, writing in the June issue of Annals of Neurology, have shed light on why predictions in facioscapulohumeral muscular dystrophy (FSHD) are particularly problematic.

A parent who is genetically “mosaic” for the FSHD mutation can pass on the mutation to his or her child, who will then have it in all cells. If the parent’s mosaic status isn’t recognized, doctors will overestimate the chances of passing on the FSHD mutation to a child. They may also underestimate the severity of the disease by assuming it will be like that of the parent.

In FSHD, the disease-causing mutation — a missing piece of DNA on chromosome 4 — isn’t always inherited. Instead, the mutation often occurs spontaneously after conception and during the early days of embryonic development.

Such mutations affect only some cells, leading to a condition called mosaicism. In FSHD, it’s not uncommon to find that only some of a person’s egg or sperm cells (germline cells) have the FSHD mutation, and only some of his or her body’s cells carry the mutation.

In general, the risk of passing on a dominant disease like FSHD is 50 percent, but this calculation is based on the parent’s having the mutation in all of his or her germline cells. If only some of these cells carry the mutation, then the risk of passing on the disease is less than 50 percent.

Of potentially greater importance, predictions of the severity of a genetic disease in a child whose FSHD-affected parent has a very mild disease can also be inaccurate.

A parent who has the mutation in only some of his or her cells may have very mild FSHD. But that person’s child would acquire the mutation through a germline cell and thus have it present in all cells starting at conception. Such a child would be more severely affected than his mosaic, partially affected parent.

The authors recommend special genetic testing called pulsed-field gel electrophoresis analysis in families in which a prospective parent is mildly affected by FSHD but whose chromosome 4 deletion would have predicted a more severe disease.

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Guidelines developed for Duchenne respiratory care

The Aug. 15 issue of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society, contains a set of guidelines about respiratory care in Duchenne muscular dystrophy (DMD). The guidelines were prepared by an ATS working group, made up of experts in DMD respiratory care.

The development of these guidelines was supported in part by MDA, through a grant to Jonathan Finder in the Department of Pulmonology at Children’s Hospital of Pittsburgh.

The recommendations should assist families in obtaining needed respiratory care from their insurers. A more complete summary can be found at

The guidelines recommend that physicians provide baseline respiratory status evaluation early in the course of DMD (between ages 4 and 6); regular consultations with a physician specializing in pediatric respiratory care; tests to evaluate pulmonary function at each clinic visit; and education about assisted ventilation options well before an emergency occurs.

Physicians are advised to regularly evaluate sleep quality and sleep-disordered breathing, cardiac status, and the ability to clear secretions (cough).

The experts say doctors should educate families in manually or mechanically assisted cough techniques when secretion clearance becomes less than adequate; and teach the use of pulse oximetry (painless measurement of blood oxygen) at home.

The guidelines recommend nighttime noninvasive ventilatory support when sleep-disordered breathing is detected; and noninvasive daytime ventilation when daytime breathing problems occur.

They suggest the option of ventilation via tracheostomy if noninvasive ventilation isn’t feasible or desired, with appropriate education for the patient and family.

They also advise evaluating pulmonary and cardiac function and sleep-related breathing before scoliosis surgery, with postoperative respiratory support and monitoring.

The ATS guidelines caution physicians to avoid using supplemental oxygen to treat sleep-related hypoventilation (inadequate breathing) unless ventilatory assistance is also being used; and to avoid starting mechanically assisted ventilation before it’s required.

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