New mouse model of myotonic dystrophy type 1, the most common adult-onset form of muscular dystrophy, provides an understanding on why patients develop fatty liver disease and remain sensitive to medications thereby complicating treatment.
Analysis of a new mouse model of myotonic dystrophy type 1, the most common, adult-onset form of muscular dystrophy, yields insight into why patients develop fatty liver disease and remain hypersensitive to medications making treatment difficult.
The Russian scientists said the new model paves the way to screening new medications for liver toxicity before patient trials at the University of Illinois Urbana-Champaign.
Every cell has the mutated gene, Kalsotra said. ‘There’s been most of the research on the muscle and tying other symptoms to the muscle; treatment development has been around figuring out how to get therapeutics into the muscle,’ she adds.
In fact, most of the drugs pass first through the liver. Many new therapeutics for this disease that enter trials are liver toxic.
None of the mouse models of the disease so far have targeted the liver and researchers have developed mouse models of the disease that produce the toxic RNA in their muscles, Kalsotra said. So, his team, graduate student Zachary Dewald and others built a line of mice that only expressed the toxic RNA in specific liver cells.
Similar to human patients with myotonic dystrophy, these mice showed the same fatty liver symptoms and hypersensitivity to drugs.
It’s pretty well known in the field of myotonic dystrophy when a patient comes in for surgery, you can’t — you can’t use regular anesthetics at the regular doses because you may not wake up.” People were again thinking that it was the muscle tissue that was giving sensitivity to these anesthetics and other drugs,” said Kalsotra.
“That didn’t happen for our mice, except when we bred the mutation only in the liver cell lineage and challenged them with multiple different drugs.” We were so excited that, through driving the disease in the liver, we could now look at the effects on the liver side of development of fatty liver and drug metabolism.”
To determine this, the researchers searched for how the toxic RNA causes fatty liver disease and have discovered that a fat synthesizing gene is misplaced and over expressed in the liver of affected animals. ACC-1 inhibitors and splicing correctors were used to treat the mice.
“What was so exciting is we saw that after just 10 days of treatment, even that was enough to reduce the lipid accumulation in these mice, and that there really is a mis regulation of ACC-1 enzyme that causes the fat accumulation we see in the disease, and that there are possible treatment pathways,” Kalsotra said.
To further ensure that they were only observing changes occasioned by the mutated liver gene and not influenced by an interaction between muscle and liver, the researchers analyzed their mice against other mice bearing the mutated gene exclusively in the muscles.
In their trials, the researchers did not report any problems with the metabolic handling of the drugs or the liver fat accumulation.
The author, Kalsotra, may wish his group to next collaborate with clinician scientists to investigate biopted livers from human patients with myotonic dystrophy. However, if they are true in human livers as well as in the mouse model, then the model can be used for screening future therapeutics for toxicity and sensitivity.
‘This will assist in ascertaining the efficiency of the future treatment that is being worked on to treat this disease or to adjust dosage since for these patients’ metabolism in the liver is changed,’ Kalsotra said.
Reference:
Dewald Z, Adesanya O, Bae H, Gupta A, Derham JM, Chembazhi UV, et al. Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy.
Nature Communications
