Graciela Gutierrez713-798-4710
HOUSTON -- (November 20, 2012) -- Muscle weakness, muscle wasting and myotonia are the most common symptoms of myotonic dystrophy type 1, but the question remains, what are the underlying mechanisms that affect this disorder. Researchers from Baylor College of Medicine are now closer to finding an answer after identifying an enzyme that when inhibited can reduce muscle weakness and myotonia in mice with the mutation for myotonic dystrophy type 1.
The findings, which appear in the current edition of The Journal of Clinical Investigation, open the door for future research into developing more effective treatment options.
Developing treatment options
"We have known that this disorder is caused by a genetic mutation that leads to accumulation of RNA repeats interfering with the function of RNA-binding proteins," said Dr. Lubov T. Timchenko, professor of molecular physiology and biophysics at BCM and lead author on the study. "What we found in this study is that these mutant repeats cause a chain reaction that leads to the increased activity of an enzyme known as GSK3ß."
Timchenko and her colleagues found that this enzyme was elevated in skeletal muscle biopsy samples from patients with myotonic dystrophy type 1 and from mouse models with the mutation. They reasoned that normalizing GSK3ß could be one way to target the disorder.
Using a GSK3ß inhibitor made up of lithium, a commonly used treatment for certain neurological disorders, researchers found that there was a reduction in muscle weakness and myotonia. They also found that if GSK3ß was inhibited in mice with the genetic mutation before symptoms began, then there was a delay in the development of muscle weakness.
Reducing muscle weakness
"This is important because myotonic dystrophy type 1 is a progressive disease. More studies are needed but these results show us that we may one day be able to begin treatment early to delay the onset of symptoms," said Timchenko.
Patients with this disorder are known to have reduced activity in a certain type of cell called myogenic satellite cells. Timchenko said in the mouse model study, the GSK3ß inhibitors worked by activating these myogenic satellite cells, which in turn reduce muscle weakness.
Researchers also noted that even when treatment was stopped, they could still see positive results in follow up examinations of myotonia. While muscle weakness and myotonia were reduced in mice, more studies are needed to determine whether damage to muscles caused by the disease can be repaired in patients with myotonic dystrophy type 1.
Understanding the symptoms
"Myotonic dystrophy type 1 has many symptoms and affects the body in different ways. We focused on the muscle weakness and myotonia because they are the most common symptoms. Before this treatment can be used for people suffering from this disorder, we must determine what else is affected by these inhibitors," Timchenko said. "While these tests are in the lab right now, the results give us a clear pathway towards clinical studies."
This study took part in collaboration with: Karlie Jones and Christina Wei, research assistants in molecular physiology and biophysics at BCM; Polina Iakova, research associate, Huffington Center on Aging at BCM; Enrico Bugiardini and Giovanni Meola, department of neurology, University of Milan; Christiane Schneider-Gold, department of neurology, St. Josef Hospital of the Ruhr-University of Bochum, Germany; James Woodgett, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Canada; James Killian, professor of neurology at BCM; and Nikolai A. Timchenko, professor with the Huffington Center on Aging at BCM.
Funding for this study came from grants from the National Institutes of Health and the French Association on Myopathies. The authors would also acknowledged rotation student John Leach, department of physiology Ph.D. program at BCM, for the initial experiments with mouse treatments.
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