Protein Gives Insight into Muscle Disorder

Protein Gives Insight into Muscle Disorder

Aug 21, 2008 2:57 PM

SALT LAKE CITY – University of Utah scientists and their collaborators have uncovered an important relationship between two proteins involved in the development of childhood muscle disorders, according to research published online this week in the Proceedings of the National Academy of Sciences.
Michael Jurynec, Ph.D., a postdoctoral fellow in human genetics, and David J. Grunwald, Ph.D., professor of human genetics, and their colleagues discovered that two previously unrelated proteins -- Selenoprotein N (SepN) and ryanodine receptors (RyR) -- both contribute to a single biochemical pathway that regulates the calcium release needed for normal muscle development and function. People with different genetic defects affecting this pathway are born with diseases of skeletal muscle weakness, otherwise known as congenital myopathies.
Prior research has shown that mutations in any of several genes, including SepN and RyR, might result in congenital myopathy, but the relationship among these different genes was unclear.
“We had no idea whether these muscle disorders arose from defects in many different kinds of pathways or from only a few commonly perturbed pathways,” says Grunwald. “By showing that two different genes linked to congenital myopathies are both involved in the same pathway, this study simplifies our thinking about the origins of these myopathies.”

Congenital myopathies linked to mutations in SepN and RyR result in a loss of muscle tone in infancy, leading to a delay in walking, and muscle weakness related to respiratory problems and joint deformities. Unfortunately, there is no screening test for these congenital myopathies before birth.

Supported in part by the University of Utah Catalyst Grant Research Program, Jurynec and his colleagues used the zebrafish, a small tropical fish in the minnow family, as a scientific model to study the roles that SepN and RyRs play in muscle development. “As a result of evolution, the proteins that control muscle development and function in fish are the same as the ones in humans,” said Jurynec, the study’s first author. “This means we can use a simple model organism like the zebrafish to gain tremendous insight into the origin of human disease.”

The problems that give rise to congenital myopathies occur when a baby is still in the womb. The zebrafish embryo is remarkably similar to the human embryo, allowing the U scientists to investigate the cellular and biochemical disturbances that occur before birth when there are mutations in SepN and RyRs. They found that both SepN and RyRs are needed for the formation of normal skeletal muscle fibers in the zebrafish. Their research also suggested that SepN modifies how well RyR functions.
“We know that mutations in the SepN gene account for a sizable fraction of congenital muscle disease patients,” says Kevin Flanigan, M.D., associate professor of human genetics and neurology at the University of Utah and a co-author of the study. “This work sheds new light on mechanisms of SepN function, and may direct us to new potential therapeutic pathways for these and other muscle diseases.”
The scientists also studied the properties of RyRs in samples of muscle tissue taken from a person with congenital myopathy. This human muscle tissue was completely lacking in SepN, and analysis of these samples revealed evidence that SepN is essential for normal activity of RyR in human muscle. Until now, this relationship between these two proteins was unknown.

There is currently no treatment for congenital myopathy other than supportive measures to preserve muscle activity and help patients cope with their symptoms. Jurynec and his colleagues did, however, make a promising discovery. When they added normal-functioning zebrafish SepN to the diseased human muscle tissue, they were able to restore some RyR activity. This striking finding suggests that RyR activity can be rescued, raising the prospect of easing disease in some congenital myopathy patients.

“It’s exciting that we were able to use a model of congenital myopathy in fish to identify a possible target for treatment of these muscle disorders in people,” said Jurynec. “Our research suggests we might be able to help people with congenital myopathy regain muscle function, even many years after their diagnosis.”

Although the congenital myopathies investigated in this study are rare diseases involving muscle associated with the skeleton, cardiac myopathies, or disorders of heart muscle, also may result from defects in calcium regulation, according to Grunwald.

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