Sex-Pronounced Cardiac Dysfunction and Electron Transport Chain Deficiency after Systemic Heterozygous Prdm16 Deletion in the Prdm16csp1/wt Mouse

Background: Genetic variants in the transcriptional regulator PR domain containing 16 (PRDM16) can cause cardiomyopathy (CMP). Recently mitochondrial dysfunction was observed in cardiac-specific Prdm16 knockout mice. However, PRDM16 role in CMP pathogenesis is mainly unresolved. Thus, we study the effects of systemic heterozygous Prdm16 deletion in Prdm16csp1/wt mice, carrying the csp1 mutation (c.888–3C>A) in a splice-acceptor site of Prdm16.

Method: Altered Prdm16 splicing in heart tissue was evaluated with endpoint PCR and quantitative PCR (qPCR) in cDNA generated from RNA isolates of murine hearts. The phenotype was evaluated by echocardiography, electrocardiography, and body composition analysis. Cardiac expression of natriuretic peptides A/B (Nppa/Nppb) and sarcomere genes was measured by qPCR. H&E and Picro-Sirius Red staining realized assessment of cardiac morphology and possible fibrosis. Cardiac mitochondria were analyzed with transmission electron microscopy (TEM) and Western Blot of selected electron transport chain (ETC) components.

Results: The csp1 mutation causes aberrant splicing and Prdm16 reduction in mutant mice. Prdm16csp1/wt mice express a mild CMP phenotype pronounced to the female sex. Cardiac hypotrophy appears. Reduced cardiac output, ejection fraction, and stroke volume illustrate diminished cardiac function. Elevated Nppb indicates cardiac stress in females. Sarcomere gene expression is unchanged. In histology cardiac structure is organized and fibrosis is absent. Mitochondrial integrity is preserved according to TEM. Strikingly, Western analysis reveals significant depletion of ETC complex IV and a tendency toward downregulation of complex I in female Prdm16csp1/wt mice.

Conclusion: Systemic heterozygous deletion of Prdm16 in mice is a valuable model for studying the PRDM16 CMP. The mild phenotype can be beneficial to identify initial disease mechanisms. This study suggests that sex is a potential modifier of the PRDM16 CMP and confirms that mitochondrial dysfunction is likely part of the pathogenesis. Further exploration of the Prdm16 deficient metabolism will help to explain the PRDM16 CMP pathogenesis.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
12 February 2022