Researchers have found what causes the wastage seen in muscular dystrophy, writes Dick Ahlstrom, Science Editor
Researchers at NUI Maynooth have for the first time explained in detail the biochemical changes that cause the muscle cell death seen in muscular dystrophy. The work could point to new drug therapies as a way to halt the muscle loss triggered by the disease.
The head of Maynooth's biology department Prof Kay Ohlendieck and graduate student Phil Doran did a painstaking study of thousands of proteins found in muscle tissue. They tracked down two key proteins that are linked to the progress of the disease.
Duchenne Muscular Dystrophy is the most common inherited muscle disease in Ireland. It is a progressive disorder that causes the weakening and degeneration of the skeletal muscles that control voluntary movement.
Duchenne mainly affects boys and is the result of mutations in the gene that regulates dystrophin, a protein that maintains the integrity of muscle fibre, explains Ohlendieck.
If there is too little dystrophin the cell membrane weakens, allowing substances to leak into and out of the cell itself.
Three years ago it was discovered that the disease allows too much calcium to enter the cell, in turn causing the cell to die. "The cell really disintegrates in an uncontrolled way," says Ohlendieck.
Using funding provided by Muscular Dystrophy Ireland and the Health Research Board, he and Doran began a three-year project to study what goes on inside a muscle cell affected by muscular dystrophy. "We used proteomics to study what happens downstream from the initial defect," says Ohlendieck.
"We wanted to see all the protein changes involved, what actually goes wrong downstream from the genetic defect."
They used gel electrophoresis to examine all the proteins expressed in the muscle cells and then mass spectroscopy to analyse a protein if it was seen to be up or down regulated. "It was a long procedure and it took a lot of time to get it going," he says. "We studied animal models which have the exact same disease."
The work gradually identified two key proteins that appear linked to disease progression, sarcalumenin and calsequestrin. "We found two major calcium-binding proteins to be down regulated in the disease."
Calcium is essential to the proper functioning of muscles. It is pumped into and out of the cells in response to stimulation by the nerve cells. In dystrophic patients however the calcium is not cleared properly and these two calcium handling proteins are implicated.
"It confirms the calcium hypothesis with muscular dystrophy," says Ohlendieck. "We found lots of other proteins up and down regulated but they were small changes that caused only minor upset within the muscle."
Knowing that these two calcium-binding proteins are involved immediately opens up opportunities for new treatments, he believes. With the involvement of calcium proven, two options include cell membrane sealing drugs or drugs that will help the cell clear out the unwanted calcium.
Ohlendieck presented the findings earlier this month at a muscular dystrophy research conference in Dublin where the latest research findings from Britain and Ireland were discussed.