Poster abstracts
Poster number 71 submitted by Zac Dewald
A hepatocellular Myotonic Dystrophy Type 1 model demonstrates an increased susceptibility towards anesthetics, drug induced liver injury and fatty liver disease in mice
Zac Dewald (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States), Andrew Gupta (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States), Auinash Kalsotra (Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, United States)
Abstract:
Myotonic Dystrophy type 1 (DM1) is multi-systemic muscular dystrophy, affecting 1 in 3000 people. DM1 is caused by a (CTG)n repeat expansion in the 3’ UTR of the ubiquitously expressed gene DMPK. The (CUG)n containing RNAs resulting from the transcription of this diseased DMPK gene aggregate in the nucleus, forming foci which sequester various RNA binding proteins (RBPs). Their sequestration in DM1 severely inhibits this maturation process in many tissues. Recent studies show that DM1 patients have increased susceptibility toward glucose intolerance, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome. Furthermore, DM1 patients are abnormally sensitive to a wide range of analgesics and anesthetics, with complications ranging from prolonged anesthesia recovery to heightened pulmonary dysfunction. These findings suggest a predisposition for liver damage and dysfunction in DM1 patients; however, this possibility has gone uninvestigated.
To understand the effects of DM1 in the liver, we generated a hepatocyte specific DM1 mouse model in which we can induce the expression of CUG containing RNA, specifically in the liver. Using these mice, we have demonstrated the disruptive effect of DM1 on the hepatocellular transcriptome and have characterized the transcriptomic changes driven by DM1 in the liver and have shown these lead to changes in liver morphology, inflammation, and necrosis. These mice also demonstrate increased lipid accumulation and the earlier onset of fatty liver disease, both on basal and high fat/high sugar diets, much like DM1 patients. Additionally, symptomology becomes worth with age, as also seen in patients with DM1. Finally using a variety of drug models, we have shown that these mice are particularly susceptible to drug induced liver injury and have difficulty clearing and recovering from anesthetics. These results support the idea that the liver plays a pivotal role in DM1 symptomology.
Keywords: Myotonic Dystrophy Type 1, Alternative splicing, RNA