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Characterisation of the Prdm16csp1/wt mouse as a model for the PRDM16 associated Cardiomyopathy ; Charakterisierung der Prdm16csp1/wt Maus als ein Modell für die PRDM16 assoziierte Kardiomyopathie
Introduction: Genetic variants of PR domain containing 16 (PRDM16) are associated with cardiomyopathy (CMP). In non-cardiac tissues, the PRDM16 protein regulates transcription, differentiation, transforming growth factor-β (TGF-β), metabolism, and mitochondrial activity. However, the pathogenesis of the PRDM16 associated CMP is largely unresolved. Recent findings suggest mitochondrial dysfunction as a possible cause. To further explore the role of PRDM16 in CMP, we used the Prdm16csp1/wt mouse model with systemic, heterozygous Prdm16 deactivation and analysed the pathophysiology and underlying molecular defects. Methods: The splice site mutation csp1 in Prdm16csp1/wt mice was evaluated with endpoint PCR, molecular cloning, high-throughput sequencing and quantitative PCR (qPCR) in heart and lung RNA. The Prdm16csp1/wt phenotype was characterised by body composition analysis, echocardiography, electrocardiography, blood pressure measurements, and respiratory analysis. Prdm16csp1/wt heart sections were stained with Picro-Sirius Red, H&E, and wheat germ agglutinin (WGA). Subsequently, sections were analysed for fibrosis, tissue organisation, and cross-sectional cardiomyocyte area. With transmission electron microscopy (TEM), the cardiac ultrastructure was assessed. Expression analysis was performed by qPCR for sarcomere genes and Natriuretic peptide B (Nppb). In addition, the heart transcriptome was analysed with high-throughput RNA sequencing. Mitochondrial and metabolic function in Prdm16csp1/wt hearts were evaluated by gas chromatography-mass spectrometry (GC-MS) of the central carbon metabolism and by Western blot analysis of the electron transport chain (ETC). Results: The csp1 mutation negatively affected splicing and reduced the Prdm16 mutant transcript level. Prdm16csp1/wt mice presented with a mild CMP phenotype, interestingly more evident in females: lower body weights, cardiac hypotrophy, diminished cardiac function, as well as normal blood pressure and respiratory function. Nppb was elevated in ...
Characterisation of the Prdm16csp1/wt mouse as a model for the PRDM16 associated Cardiomyopathy ; Charakterisierung der Prdm16csp1/wt Maus als ein Modell für die PRDM16 assoziierte Kardiomyopathie
Introduction: Genetic variants of PR domain containing 16 (PRDM16) are associated with cardiomyopathy (CMP). In non-cardiac tissues, the PRDM16 protein regulates transcription, differentiation, transforming growth factor-β (TGF-β), metabolism, and mitochondrial activity. However, the pathogenesis of the PRDM16 associated CMP is largely unresolved. Recent findings suggest mitochondrial dysfunction as a possible cause. To further explore the role of PRDM16 in CMP, we used the Prdm16csp1/wt mouse model with systemic, heterozygous Prdm16 deactivation and analysed the pathophysiology and underlying molecular defects. Methods: The splice site mutation csp1 in Prdm16csp1/wt mice was evaluated with endpoint PCR, molecular cloning, high-throughput sequencing and quantitative PCR (qPCR) in heart and lung RNA. The Prdm16csp1/wt phenotype was characterised by body composition analysis, echocardiography, electrocardiography, blood pressure measurements, and respiratory analysis. Prdm16csp1/wt heart sections were stained with Picro-Sirius Red, H&E, and wheat germ agglutinin (WGA). Subsequently, sections were analysed for fibrosis, tissue organisation, and cross-sectional cardiomyocyte area. With transmission electron microscopy (TEM), the cardiac ultrastructure was assessed. Expression analysis was performed by qPCR for sarcomere genes and Natriuretic peptide B (Nppb). In addition, the heart transcriptome was analysed with high-throughput RNA sequencing. Mitochondrial and metabolic function in Prdm16csp1/wt hearts were evaluated by gas chromatography-mass spectrometry (GC-MS) of the central carbon metabolism and by Western blot analysis of the electron transport chain (ETC). Results: The csp1 mutation negatively affected splicing and reduced the Prdm16 mutant transcript level. Prdm16csp1/wt mice presented with a mild CMP phenotype, interestingly more evident in females: lower body weights, cardiac hypotrophy, diminished cardiac function, as well as normal blood pressure and respiratory function. Nppb was elevated in ...
Characterisation of the Prdm16csp1/wt mouse as a model for the PRDM16 associated Cardiomyopathy ; Charakterisierung der Prdm16csp1/wt Maus als ein Modell für die PRDM16 assoziierte Kardiomyopathie
Theisen, Simon (author) / male / N.N.
2024-01-01
Theses
Electronic Resource
English
Androgen Receptor is a Negative Regulator of PRDM16 in Beige Adipocyte (Adv. Sci. 21/2023)
| Wiley | 2023
| TIBKAT | 2010