Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy
Abstract Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liv...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53378-z |
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| author | Zachary Dewald Oluwafolajimi Adesanya Haneui Bae Andrew Gupta Jessica M. Derham Ullas V. Chembazhi Auinash Kalsotra |
| author_facet | Zachary Dewald Oluwafolajimi Adesanya Haneui Bae Andrew Gupta Jessica M. Derham Ullas V. Chembazhi Auinash Kalsotra |
| author_sort | Zachary Dewald |
| collection | DOAJ |
| description | Abstract Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment. |
| format | Article |
| id | doaj-art-1ca2402046454b8dbc0d8bced85796d8 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1ca2402046454b8dbc0d8bced85796d82025-08-20T02:11:18ZengNature PortfolioNature Communications2041-17232024-10-0115111810.1038/s41467-024-53378-zAltered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophyZachary Dewald0Oluwafolajimi Adesanya1Haneui Bae2Andrew Gupta3Jessica M. Derham4Ullas V. Chembazhi5Auinash Kalsotra6Department of Biochemistry, University of Illinois, Urbana-ChampaignDepartment of Biochemistry, University of Illinois, Urbana-ChampaignDepartment of Biochemistry, University of Illinois, Urbana-ChampaignDepartment of Biochemistry, University of Illinois, Urbana-ChampaignDepartment of Biochemistry, University of Illinois, Urbana-ChampaignDepartment of Biochemistry, University of Illinois, Urbana-ChampaignDepartment of Biochemistry, University of Illinois, Urbana-ChampaignAbstract Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment.https://doi.org/10.1038/s41467-024-53378-z |
| spellingShingle | Zachary Dewald Oluwafolajimi Adesanya Haneui Bae Andrew Gupta Jessica M. Derham Ullas V. Chembazhi Auinash Kalsotra Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy Nature Communications |
| title | Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy |
| title_full | Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy |
| title_fullStr | Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy |
| title_full_unstemmed | Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy |
| title_short | Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy |
| title_sort | altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy |
| url | https://doi.org/10.1038/s41467-024-53378-z |
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