Researchers from the University of Illinois Urbana-Champaign have developed a new mouse model that replicates liver issues associated with myotonic dystrophy type 1, the most common adult-onset muscular dystrophy. This innovative model sheds light on the reasons behind the occurrence of fatty liver disease in patients and their heightened sensitivity to medications, which complicates treatment options. It also allows for the testing of new drugs for liver safety before they are used in human trials.
Under the guidance of biochemistry professor Auinash Kalsotra, the researchers detailed their work in the journal Nature Communications.
“Myotonic dystrophy is not just limited to muscle issues; it affects multiple systems. The mutated gene is present in every cell,” Kalsotra explained. “Research has largely focused on muscle, often linking other symptoms back to muscle problems. Consequently, treatment has aimed at delivering drugs to muscle tissue. However, since most medications first pass through the liver, many of these new treatments show toxicity there. Understanding liver processes is crucial.”
This disease results from a mutation in the DMPK gene, characterized by a CTG sequence that can repeat from dozens to thousands of times. Although this region does not code for a protein, it produces harmful RNA that accumulates in the nuclei of cells. The repeated sequence causes the RNA to form tight hairpin loops, which interact with and disrupt a group of RNA-binding proteins that play a role in the splicing of other RNAs and proteins.
Previously developed mouse models have successfully shown toxic RNA production in muscle, but a model specifically targeting the liver was lacking, Kalsotra noted. His team, including graduate student Zachary Dewald, created a mouse line producing the toxic RNA strictly in liver cells. These mice exhibited similar fatty liver symptoms and drug hypersensitivity that are often observed in human patients with myotonic dystrophy.
“In the field of myotonic dystrophy, it’s well recognized that standard anesthetics cannot be used at normal dosages for patients undergoing surgery, as it may prevent them from waking up. While many believed this sensitivity stemmed from muscle tissue, our findings show that even with the mutation expressed only in liver cells, the mice displayed drug sensitivities. This discovery excited us as it allows us to observe how liver effects influence both fatty liver progression and drug metabolism,” Kalsotra remarked.
In their quest to understand why the toxic RNA leads to fatty liver disease, the researchers found that a gene responsible for fat synthesis, known as ACC-1, is incorrectly spliced and overactive in the affected livers. They experimented with ACC-1 inhibitors and splicing correctors on the mice.
After just 10 days of treatment, they observed a reduction in fat accumulation within these mice, indicating that the misregulation of the ACC-1 enzyme is responsible for the fat buildup associated with the disease. This opens potential avenues for treatments,” Kalsotra stated.
To ensure that the observed effects were exclusively due to liver involvement and not influenced by muscle, the researchers contrasted their findings with another mouse line where the mutated gene was expressed solely in muscle. They found no signs of issues with drug metabolism or fatty liver development in those mice.
“These results underscore the significance of examining the impacts of myotonic dystrophy on individual tissues and assessing their roles in the metabolic dysfunction evident in these patients,” Kalsotra emphasized. “We must avoid focusing solely on one tissue type and neglecting others.”
Kalsotra aspires for his research group to collaborate with clinicians to examine liver biopsy samples from human myotonic dystrophy patients. If the adverse conditions seen in the human liver are aligned with those in the mouse model, this could provide a valuable tool for screening future drug therapies for potential toxicity and sensitivity.
“This could help ensure that new treatments developed for this condition are effective and that drug dosages can be adjusted, considering the altered liver metabolism seen in these patients,” Kalsotra concluded.
This research was supported by the National Institutes of Health, the Muscular Dystrophy Association, the Chan-Zuckerberg Biohub Chicago, and the Beckman Fellowship from the Center for Advanced Study at the University of Illinois. Co-authors on the study included Dewald, postdoctoral researcher Haneui Bae, graduate students Oluwafolajimi Adesanya, Jessica Derham, Ullas Chembazhi, and undergraduate student Andrew Gupta.
