Poster abstracts
Poster number 23 submitted by Zac Dewald
Myotonic Dystrophy Type 1 Adversely Alters the Adult Hepatocellular Transcriptome
Zachary Dewald (Biochemistry-University of Illinois Urbana Champaign), Auinash Kalsotra (Biochemistry-University of Illinois Urbana Champaign)
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). The most pivotal RBPs sequestered are the muscleblind-like (MBNL) family proteins, a group of splicing factors that play significant roles in the juvenile-to-adult development of many tissues. 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 various 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. Through these mice, we have shown the presence of the toxic RNA in hepatocytes sequesters Mbnl proteins, causing a reduction in mature hepatocellular activity. We have characterized the transcriptomic changes driven by DM1 in the liver and have shown that these lead to changes in liver morphology, inflammation, necrosis, and increased lipid accumulation. We have demonstrated that DM1 sensitizes the liver to poor diet, increasing the likelihood of NAFLD development when patients consume high fat, high sugar diets. We have utilized the mouse models to demonstrate that DM1 adversely affects drug metabolism, slowing drug clearance and making patients more sensitive to potentially lethal anesthetics and analgesics. Finally, we have shown that divergence from appropriate adult hepatocellular function caused by DM1 increases with age, like other tissues affected by DM1.
Keywords: Myotonic Dystrophy Type 1, Alternative Splicing , Liver