Muslce Bound
Clarifying the steps causing muscle-fiber degeneration brings scientists closer to the eureka point for inclusion-body myositis and, perhaps, for Alzheimer’s disease.
If you stop to think about it, it is not all that surprising that the most common progressive muscle disease in older people appears to have strong parallels to the most common form of dementia in seniors, even though the two diseases are not linked in any way.
The dementia in question is Alzheimer’s; the muscle disease is a widespread but relatively unknown condition called inclusion-body myositis, or IBM. And according to research recently published in The Lancet by a team of Keck School of Medicine of USC scientists, a key aspect of their similarity seems to be the increasingly notorious protein fragment, amyloid-ß, which accumulates in the hard, insoluble plaques often thought of as the hallmark of Alzheimer’s disease.
Specifically, Valerie Askanas, M.D., Ph.D., W. King Engel, M.D., and their Keck School colleagues found that two enzymes involved in the production of amyloid-ß are increased inside the muscle cells of patients with IBM. They previously found that amyloid-ß itself and its precursor protein AßPP are increased inside IBM muscle fibers.
Those two enzymes are BACE1 and BACE2, which selectively snip the AßPP to create the presumably toxic amyloid-ß; they are found in normal tissues only at very low levels. Until now, they have not been shown to be increased in any diseased tissue.
“We have found an increase at the protein level of these two enzymes for the first time ever in a human disease,” explains Askanas, the paper’s principal investigator and a professor of neurology and pathology at the Keck School.
IBM is a crippling disease, usually beginning in people over age 50, in which the muscle tissue develop inflammation and muscle fibers atrophy—but in which the brain is spared and patients retain their full intellect. “Patients with IBM become very frustrated because they begin falling suddenly, can’t grip things and—with progression—can’t get up and walk,” says Engel, a Keck School professor of neurology and pathology. “One of my patients is a carpenter who now won’t hammer because he’s afraid the hammer will fly out of his hand. This is a very insidious, progressive disease.”
The discovery of the increase in the two BACE enzymes, notes Askanas, means that treatment for this disease may not be as out of reach as it has been in the past. “If factors can be found that can decrease the enzyme, then hopefully amyloid-ß protein would no longer be produced in toxic amounts,” she explains.
And potentially, this approach could also be useful to the millions of aging Americans who have or will develop Alzheimer’s disease.
Not only do the pathogenic pathways of the two diseases, in muscle and brain, have similarities, but the muscle fibers that are affected in IBM patients are fairly easy to culture and investigate.
“Muscle is a fantastic model that can be used to more easily study amyloid-ß accumulation, as compared to the brain,” says Askanas, who recently received a MERIT award from the National Institute of Aging at the National Institutes of Health to study IBM and its relationship to Alzheimer’s disease.
“You can’t take brain cells from Alzheimer’s patients and manipulate them to see what happens when you decrease or increase these enzymes. But we are doing that in IBM studies—we can take fresh muscle biopsies, culture them and generate IBM-like affected muscle cells using the molecular genetics of AßPP gene transfer.
“The muscle cells in culture express BACE and are a very good living model of the IBM disease,” she adds. “This makes it much easier to experimentally modulate the amount of BACE in the cells actually affected—to up-regulate it, to down-regulate it, to do genetic engineering, to look for potentially therapeutic maneuvers that will lessen or stop the disease process.”
And that is exactly what Askanas and her colleagues are planning to do.
In fact, they have already collected data showing that cholesterol—for reasons as yet unknown—may increase production of the unwelcome amyloid-ß protein in human muscle culture, and similarly, that cholesterol is found deposited inside IBM degenerating muscle fibers in the same places as the pathologic, small plaques of amyloid-ß protein. “So there is a direct correlation between cholesterol and amyloid-ß deposition,” Askanas says. “That may be relevant not only to IBM; other researchers have reported that persons who are treated with cholesterol-lowering drugs have a lower incidence of Alzheimer’s disease. Now we are going to set up a study to see what happens to BACE when the cultured muscle is experimentally burdened with added cholesterol and, conversely, when treated with drugs to inhibit its cholesterol synthesis.”
“Patients always want to know the bottom line,” adds Engel. “Is there a new treatment? Not yet. But we can’t develop a new treatment until we better understand the steps of pathogenesis causing the muscle-fiber degeneration. This paper will play an important role in clarifying those steps. All of these things Dr. Askanas and her team are doing are bringing us closer to the eureka point for IBM and, perhaps, for Alzheimer’s disease.”
And according to patients with IBM and related diseases such as polymyositis and dermatomyositis, the researchers’ pursuit of new ideas and treatments for their conditions inspire people to move—or, more literally, to climb—mountains to help them along. That is why, this July, a team of 11 climbers, each of whom has pledged to raise a minimum of $10,000 in sponsorship, will be attempting a six-day ascent of Tanzania’s 19,340-foot Mt. Kilimanjaro. Each climber is dedicating their climb to a myositis patient—an “honoree”—and the money they raise will be donated to the USC Neuromuscular Center to fund the work of Askanas and Engel, says Laurel Colton, Ph.D., the event’s coordinator. Colton says she chose Askanas and Engel to receive the money because they are “forerunners in the field of myositis research. They have published and lectured widely on the subject and have made major contributions to the medical community’s understanding of this terrible disease
Colton’s mother, June, who is one of Laurel’s three honorees and a long-time patient of Engel’s, said she can’t think of anyone more deserving of this effort than Engel and Askanas. “This is their life’s work,” she says. “They’re the best in the world. When you’re giving your money to research, why wouldn’t you give it to the best?”
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