Research Updates Winter 2011

Article Highlights:

The latest research as of December 2010:

by Quest Staff on January 1, 2011 - 1:44pm

QUEST Vol. 18, No. 1

Sildenafil helps heart in mice lacking dystrophin

Researchers have found that treatment with sildenafil (Viagra) conferred long-term protection against cardiac dysfunction in young mice with a disease resembling Duchenne muscular dystrophy (DMD) and reversed the heart damage in aged mice with this condition. The mice lacked dystrophin, the protein missing in humans with DMD and deficient in those with Becker muscular dystrophy (BMD).

The research team, which included MDA grantee Justin Percival at the University of Washington-Seattle, published its findings online Oct. 18, 2010, in Proceedings of the National Academy of Sciences.

Sildenafil belongs to a class of drugs called phosphodiesterase 5 (PDE5) inhibitors and is designed to relax the smooth muscles that line blood vessels, an effect that may improve blood flow to skeletal muscles and the heart. Sildenafil is marketed in the United States under the brand name Viagra for erectile dysfunction and under the name Revatio for pulmonary arterial high blood pressure.

Tadalafil, another PDE5 inhibitor, is being studied for its possible effect on skeletal muscle function in men with BMD. Revatio is being studied for its possible effect on cardiac function in adolescents and men with DMD. (See Clinical Trials and Studies.)

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Decoy receptor lures myostatin, increases strength of DMD mice

Luring away myostatin and possibly other proteins that restrict muscle growth, using a gene for a “decoy receptor,” increases muscle size and strength in mice with a disease resembling Duchenne muscular dystrophy (DMD), scientists have found.

Kevin Morine at the University of Pennsylvania, with colleagues there and elsewhere, announced their findings online Aug. 20, 2010, in Muscle & Nerve.

The research builds on earlier findings that cows and humans naturally deficient in myostatin (a protein that inhibits muscle growth) develop large muscles, and that various strategies for interfering with myostatin can build muscle in mice.

Acceleron Pharma is testing an anti-myostatin strategy in boys with DMD in Canada, using an experimental drug called ACE031. (See Clinical Trials and Studies.)

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New CMD mouse model expected to speed research

Researchers have created a mouse model of two types of congenital muscular dystrophy (CMD), known as muscle-eye-brain disease (MEB) and Walker-Warburg syndrome (WWS). Both types can result from mutations in the fukutin-related protein gene. The new research mouse has a mutation in the fukutin-related protein gene and develops brain, eye and skeletal muscle defects similar to those seen in MEB and WWS. It’s hoped the new mouse model will help speed research in these diseases. Qi Lu at Carolinas Medical Center in Charlotte, N.C., coordinated the study team, which published its findings in the Oct. 15, 2010, issue of Human Molecular Genetics.

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New MDA grants awarded

MDA recently approved funding totaling approximately $13.5 million for more than 40 new grants targeted at stopping muscular dystrophies and related neuromuscular diseases.

MDA’s Board of Directors met Dec. 10, 2010, in New York City, where it reviewed and approved the new grants based on recommendations from the MDA Scientific and Medical Advisory Committees. Applications were scored and recommended for approval based on the capabilities of the applicant, the scientific merit of the project, and the proposal’s relevance to understanding and developing treatments for the disease.

The new grants support research in ALS; Becker and Duchenne muscular dystrophies; centronuclear myopathies; congenital muscular dystrophy; Charcot-Marie-Tooth disease; Friedreich’s ataxia; inclusion-body myositis; Lambert-Eaton syndrome; limb-girdle muscular dystrophy; myasthenia gravis; mitochondrial myopathy; myotubular myopathy; myotonia congenita; myotonic dystrophy; spinal-bulbar muscular atrophy; and spinal muscular atrophy.

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Early-life protein, made too late, leads to FSHD

A protein known as DUX4, normally active only during early development, appears to be present much later in life than is usual in the muscles and possibly other tissues of people with facioscapulohumeral muscular dystrophy (FSHD), new research has shown.

A research team that received MDA support has discovered that the changes on chromosome 4 that underlie FSHD apparently allow for prolonged and probably harmful production of DUX4. The research team included many of the same members who recently announced that two genetic changes are needed to cause FSHD (see Research Updates, October-December 2010; and the Quest Mailbag letter).

Stephen Tapscott at the Fred Hutchinson Cancer Research Institute in Seattle coordinated the research group, which published its findings online Oct. 28, 2010, in PLoS Genetics. The new findings “validate DUX4 as a target for future FSHD therapies,” Tapscott said.

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Researchers ID mechanism that regulates the protein deficient in FA

Scientists have identified two proteins and a specific DNA sequence in the frataxin gene that work together to regulate production levels of frataxin protein. Frataxin is deficient in Friedreich’s ataxia (FA), and the findings could provide a new approach to increasing its synthesis.

Kuanyu Li at Nanjing (China) University and Tracey Rouault at the National Institute of Child Health and Human Development in Bethesda, Md., coordinated the study team, which published its findings online Aug. 20, 2010, in PLoS One. (For more on FA, see "In Focus: Friedreich's Ataxia," Quest, January-March 2011.)

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Overactive protein causes motor neuron death in SBMA

Overactivity of a normal androgen receptor protein, and its interactions with disease-modifying “partner” proteins, have been implicated as the specific underlying cause of the degeneration of the motor neurons (muscle-controlling nerve cells) in spinal-bulbar muscular atrophy (SBMA), also called Kennedy disease.

The investigation, which received MDA support, opens the possibility of developing SBMA therapies that selectively target problematic androgen receptor protein interactions.

A mutinational team of researchers that included Maria Pennuto at the Italian Institute of Technology in Genova, Italy, and J. Paul Taylor at St. Jude Children’s Research Hospital in Memphis, Tenn., collaborated on this study, publishing its findings online Sept. 23, 2010, in Neuron.

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Low SMN and low alpha-synuclein go together in SMA

A research group that included MDA grantee Gyula Acsadi at Wayne State University in Detroit has found that deficiencies of SMN, the underlying cause of most cases of spinal muscular atrophy (SMA), are associated with reduced levels of alpha-synuclein, a protein believed to be involved in protection of nerve cells and nerve-cell signal transmission. The findings could provide an important clue in understanding SMA.

Graham Parker at Wayne State coordinated the team, which published its findings online July 17, 2010, in the Journal of Molecular Neuroscience.

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Gene defect for rare form of SMA is linked to chromosome 14

A large, North American family with a dominantly inherited type of spinal muscular atrophy (SMA) was found to have SMA arising from a genetic mutation in a specific region of chromosome 14. Most SMA is recessively inherited and arises from mutations in the SMN gene on chromosome 5. Robert Baloh at Washington University in St. Louis coordinated the study team, which was supported in part by MDA and published its findings in the Aug. 10, 2010, issue of Neurology.

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New genetic cause of nemaline myopathy identified

Mutations in the gene for a protein called KBTBD13 can be added to the list of various gene mutations that can cause nemaline myopathy, a disease characterized by muscle weakness usually starting in infancy or childhood and thread- or rodlike (nemaline) bodies in affected muscles.

Nyamkhishig Sambuughin at Uniformed Services University in Bethesda, Md., coordinated the study team, which included researchers in the United States, Australia, Spain and the Netherlands and published its findings in the Dec. 10, 2010, issue of the American Journal of Human Genetics.

In this and earlier studies, the researchers included Dutch, Australian-Dutch, Australian-Belgian and Spanish patients, finding they all had a dominantly inherited muscle disease linked to an unknown gene on chromosome 15. They also had poor exercise tolerance, slowness of movements, gait abnormalities and slowly progressive weakness of the neck and upper limb muscles starting in childhood. Muscle biopsy samples showed nemaline rods.

Previously identified causes of nemaline myopathy include mutations in the genes for the proteins known as alpha-actin, alpha-tropomyosin, beta-tropomyosin, troponin T, nebulin and cofilin 2. Each of these proteins is part of or affects the assembly of sarcomeres, the contracting parts of muscle fibers. The KBTBD13 protein, however, has an as-yet-unknown role in muscle structure or function, leading the investigators to speculate that the disease mechanism in KBPBD13-related nemaline myopathy may be different from the sarcomere-related mechanisms underlying other forms of this disease.

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