A new mouse model that mimics the liver symptoms of myotonic dystrophy type 1 (the most common form of adult-onset muscular dystrophy) is providing insight into why patients develop fatty liver disease and show hypersensitivity to drugs, complicating treatment. University of Illinois Urbana-Champaign researchers said the new model opens avenues for screening new drugs for liver toxicity before patient trials.

Researchers led by U. of I. biochemistry professor Auinash Kalsotra published their research. findings in the magazine Nature Communication.

“This disease is just muscle disease; It is a multisystemic disease. “The mutated gene is present in every cell,” Kalsotra said. “Most of the research has focused on the binding of other symptoms to muscles or muscles, and treatment development has been about how to deliver therapeutics to muscles. But most drugs go directly to the liver first. As new treatments for this disease come into trials, many show: liver toxicity. So we need to understand what’s happening in the liver.”

The disease is caused by a mutation in the DMPK gene. A three-letter CTG sequence is repeated dozens to thousands of times. Although it is in the part that does not code for a protein, it is translated into toxic RNA that accumulates in the cell nucleus. The repeated sequence causes the RNA to form tight hairpin loops; this is a structure that binds to and interferes with a class of RNA-binding proteins that regulate how other RNAs and proteins bind to each other.

Kalsotra said researchers have developed mouse models of the disease that produce toxic RNA in their muscles, but none target the liver. His team, led by graduate student Zachary Dewald, developed a line of mice that specifically produced the toxic RNA in their bodies. liver cells. These mice exhibited the same fatty liver symptoms and drug hypersensitivity often seen in human patients with myotonic dystrophy.

“It’s well known in the field of myotonic dystrophy that when a patient comes in for surgery, you can’t use regular anesthetics in regular doses because they may not wake up. But still, people have thought that increased sensitivity to these anesthetics and other drugs is driven by muscle tissue” said Kalsotra.

“But our mice, in which the mutation was expressed only in liver cells and not in any other cell type, showed sensitivity when we challenged them with various drugs. So we were very excited that we could now see the effects of the disease by driving the disease in the liver. Its effects on both fatty liver development and drug metabolism.”

While investigating the mechanism of why toxic RNA arises fatty liver diseaseThe researchers found that ACC-1, a gene that regulates fat synthesis, was misspliced ​​and upregulated in affected livers. They treated mice with ACC-1 inhibitors and splicing correctors.

“We found that just 10 days of treatment could reduce lipid accumulation in these mice, which tells us that misregulation of the ACC-1 enzyme is actually causing the fat accumulation we see in the disease, and that there are possible treatments available,” Kalsotra said. in question.

To confirm that the effects they saw were driven solely by the liver rather than muscle interaction, the researchers compared their mice with another strain of mice that expressed: mutated gene only in muscle tissue. Researchers did not observe any problems with drug metabolism or the development of fatty liver.

“These findings really highlight the importance of examining the effects of myotonic dystrophy in individual tissues and then assessing their contribution to the metabolic dysfunction seen in these patients,” Kalsotra said. “We can’t just focus on one tissue type and completely ignore the others.”

Kalsotra hopes his group will next partner with clinicians to examine biopsied liver tissue from human patients. myotonic dystrophy. If the pathology in human livers is confirmed to match that seen in the following example: mouse modelThe model may be useful for screening future therapeutics for toxicity and sensitivity.

“This will help us ensure the effectiveness of prospective therapies being developed to treat this disease and adjust dosages accordingly, keeping in mind that metabolism in the liver is altered for these patients,” Kalsotra said.