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Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 to inhibit AMPK activity and induce mitochondrial dysfunction

ABSTRACT: To analyze the mRNA profile of DUBs in diabetic heart, we performed a scRNA-seq of heart cells from the wild type (WT) mice and db/db mice, a typical T2DM model mouse.

ORGANISM(S): Mus musculus

PROVIDER: GSE290932 | GEO | 2025/06/11

REPOSITORIES: GEO

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Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 to inhibit AMPK activity and induce mitochondrial dysfunctionCardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 to inhibit AMPK activity and induce mitochondrial dysfunction

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Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 to inhibit AMPK activity and induce mitochondrial dysfunction

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Molecular Mechanism of type 2 diabetes mellitus-mediated heart failure with preserved ejection fraction

Project description:Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with several comorbidities, including cardiac dysfunction leading to heart failure with preserved ejection fraction (HFpEF), in turn resulting in T2DM-induced cardiomyopathy (T2DM-CM). However, the molecular mechanisms underlying the development of T2DM-CM are poorly understood. It is hypothesized that molecular alterations in myopathic genes induced by diabetes promote the development of HFpEF, whereas cardiac myosin inhibitors can rescue the resultant T2DM-induced cardiomyopathy. To test this hypothesis, a Leptin receptor-deficient db/db homozygous (Lepr db/db) mouse model was used to define the pathogenesis of T2DM-CM. Echocardiographic studies at 4 and 6 months revealed that Lepr db/db hearts started developing cardiac dysfunction by four months, and left ventricular hypertrophy with diastolic dysfunction was evident at 6 months. Strikingly, the level of cardiac myosin binding protein-C phosphorylation was significantly increased in Lepr db/db mouse hearts. RNA-seq data analysis, followed by functional enrichment, revealed the differential regulation of genes related to cardiac dysfunction in Lepr db/db heart tissues. Finally, using isolated skinned papillary muscles and freshly isolated cardiomyocytes, CAMZYOS (mavacamten, which is a prescription heart medicine used for symptomatic obstructive hypertrophic cardiomyopathy treatment (herein after denotes as MYK-461), was tested for its ability to rescue T2DM-CM. Compared with controls, MYK-461 significantly reduced force generation in papillary muscle fibers and cardiomyocyte contractility in the db/db group. This line of evidence shows that 1) T2DM-CM is associated with hyperphosphorylation of cardiac myosin binding protein-C and 2) MYK-461 significantly lessened disease progression, suggesting its promise as a therapeutic treatment for HFpEF.

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Transcriptomic study of heart tissue from diabetic cardiomyopathy mice

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Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [CRISPR]

Project description:The ubiquitination and proteasome-mediated degradation of Hypoxia Inducible Factors (HIFs) is central to metazoan oxygen-sensing, but the involvement of deubiquitinating enzymes (DUBs) in HIF signalling is less clear. Here, using a bespoke DUBs sgRNA library we conduct CRISPR/Cas9 mutagenesis screens to determine how DUBs are involved in HIF signalling. Alongside defining DUBs involved in HIF activation or suppression, we identify USP43 as a DUB required for efficient activation of a HIF response. USP43 is hypoxia regulated and selectively associates with the HIF-1 isoform, and while USP43 does not alter HIF-1 stability, it facilitates HIF-1 nuclear accumulation and binding to its target genes. Mechanistically, USP43 associates with 14-3-3 proteins in a hypoxia-dependent manner to increase the nuclear pool of HIF-1, independently of DUB activity. Together, our results unveil the DUB landscape in HIF signalling, and highlight the multifunctionality of DUBs, illustrating that they can provide important signalling roles outside of their catalytic activity.

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Deubiquitinating enzyme mutagenesis screens identify a USP43 driven HIF-1 transcriptional response [RNA-seq]

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