Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Heterozygous Prdm16 deactivation in mice induces cardiomyopathy and affects cardiac metabolism
J. Kühnisch1, J. Dartsch1, S. Theisen1, R. Fritsche-Guenther2, A. Bauer2, A.-K. Kahlert3, J. Kirwan2, C. MacRae4, N. Hubner5, S. Klaassen1
1Experimental & Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin, Berlin; 2Berlin Institute of Health Metabolomics Platform, Berlin Institute of Health (BIH), Berlin; 3Klinik für angeborene Herzfehler und Kinderkardiologie, Universitätsklinikum Schleswig-Holstein, Kiel; 4Cardiovascular Division, Harvard Medical School and Harvard Stem Cell Institute, Cambridge, US; 5Max Delbrück Center for Molecular Medicine (MDC), Berlin;

Cardiomyopathy and heart failure leads to life-threatening conditions and can be caused by genetic defects. One example of a primary cardiomyopathy is the PR/SET domain 16 (PRDM16) gene associated human cardiomyopathy. Genetic truncating or missense variants in PRDM16 cause dilated and left ventricular non-compaction cardiomyopathy. Here, we explore the cleft secondary palate 1 (Prdm16csp1/wt) mouse as preclinical disease models for the PRDM16 associated cardiomyopathy. We characterize the heart phenotype of Prdm16csp1/wt mice and perform molecular analysis of the heart tissue.

 

            In the systemic, germline Prdm16csp1/wt strain the splice acceptor site mutation c.888-3C>A in intron 6-7 induces a truncated, instable Prdm16 protein of 343 amino acid length (ENSMUST00000030902.12). Heterozygous 8-month-old Prdm16csp1/wt mice are viable, demonstrate with significantly reduced body weight (BW), relative heart weight (HW/TL), and relative left ventricular heart weight (LVW/TL). Echocardiography revealed in Prdm16csp1/wt mice diminished cardiac output (CO), ejection fraction (EF), and stroke volume (SV). The cardiac hypotrophy and physiological heart constraint were more pronounced in female Prdm16csp1/wt mice. Cardiac hypotrophy of Prdm16csp1/wt mice is explained by mildly diminished cardiomyocyte size, while the overall heart tissue organization appears normal. RNAseq analysis of heart tissue identifies 28 and 90 differentially expressed transcripts in males and female Prdm16csp1/wt mice, respectively. Between both sexes Prdm16, Ladinin-1 (Lad1), and UbiA prenyltransferase domain-containing 1 (Ubiad1) transcripts are consistently upregulated. Metabolic analysis revealed diminished levels of compounds involved in amino acid, glycerol, glycolysis, and tricarboxylic acid metabolism. However, steady-state levels of major lipid classes remain unaffected in Prdm16csp1/wt mice. On protein level these alterations were accompanied with mammalian target of rapamycin (mTOR) activation in Prdm16csp1/wt mice and selective degradation of proteins composing the mitochondrial electron transport chain. These observations suggest a switched metabolism upon Prdm16 deactivation in the heart.

 

This work establishes Prdm16csp1/wt mice as viable preclinical models facilitating mechanistic and therapeutic studies for the PRDM16 associated cardiomyopathy. Molecular analysis suggests a critical role of Prdm16 for cardiac metabolism probably leading to cardiomyopathy.


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