Sustainable recovery of MBNL activity in autoregulatory feedback loop in myotonic dystrophy

Rogalska, Zuzanna; Sobczak, Krzysztof

doi:10.1016/j.omtn.2022.10.023

Cited by 3 publications

(3 citation statements)

References 49 publications

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“…The upregulation of MBNL2 might explain why there is lower-than-expected overlap between changes in the Mbnl1 KO and DM1 liver models. Additionally, the increase of MBNL2 implies a compensatory mechanism that buffers the effects of Mbnl1 loss within the liver, a mechanism demonstrated in other tissues 34,35 .…”

Section: Resultsmentioning

confidence: 91%

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Altered drug metabolism and increased susceptibility to fatty liver disease in myotonic dystrophy

Dewald

Gupta

et al. 2021

Preprint

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Myotonic Dystrophy type 1 (DM1) is multi-systemic muscular dystrophy, affecting 1 in 3000 people, characterized by muscle wasting, myotonia, cardiac and gastrointestinal abnormalities and cognitive impairment, among other symptoms. 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 muscleblind-like (MBNL) family proteins, a group of splicing factors that play significant roles in the juvenile-to-adult development of 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. Through these mice, we demonstrate that the expression of the toxic RNA in hepatocytes sequesters MBNL proteins, causing a reduction in mature hepatocellular activity, however, we find that, in contrast to other tissues, loss of MBNL1 activity only reproduces a small portion of the transcriptome changes in DM1 afflicted hepatocytes. We characterized the transcriptomic changes driven by DM1 in the liver and show that these lead to changes in hepatocellular morphology, inflammation, and necrosis, as well as excessive lipid accumulation and fatty liver disease. We further demonstrate that DM1 mice livers are defective in drug metabolism and clearance, and when challenged, exhibit marked impairment against zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. Together, these results reveal that the expression of CUG repeat containing RNA disrupts the normal hepatic functions and predisposes the liver to injury, fatty liver disease, and drug clearance pathologies that may jeopardize the health of DM1 patients and complicate the treatment of DM1.

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Section: Resultsmentioning

confidence: 91%

“…Additionally, the increase of MBNL2 implies a compensatory mechanism that buffers the effects of Mbnl1 loss within the liver, a mechanism demonstrated in other tissues 34,35 .…”

Section: Expression Of Cug960i Rna Induces Global Transcriptomic Chan...mentioning

confidence: 94%

Altered drug metabolism and increased susceptibility to fatty liver disease in myotonic dystrophy

Dewald

Gupta

et al. 2021

Preprint

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“… 28 Its mammalian homolog, muscleblind-like (MBNL), is involved in neuromuscular disorders such as myotonic dystrophy type1 (DM1), and sustainable recovery of MBNL activity in an autoregulatory feedback loop shows some benefits in cells derived from patients with DM1. 29 , 30 MBNL has three isoforms with distinct functions. 31 Notably, the expression of mbl was not changed in the presynaptic neuron (pattern 2) RNA-seq data ( Figures 2 B and S2 A2; Table S1 ).…”

Section: Resultsmentioning

confidence: 99%

Identifying new players in structural synaptic plasticity through dArc1 interrogation

Xiao,

M’Angale,

Wang

et al. 2023

iScience

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Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy

Dewald,

Adesanya,

Bae

et al. 2024

Nat Commun

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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.

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Sustainable recovery of MBNL activity in autoregulatory feedback loop in myotonic dystrophy

Cited by 3 publications

References 49 publications

Altered drug metabolism and increased susceptibility to fatty liver disease in myotonic dystrophy

Altered drug metabolism and increased susceptibility to fatty liver disease in myotonic dystrophy

Identifying new players in structural synaptic plasticity through dArc1 interrogation

Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy

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