Prdm16mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators

BackgroundMutation of thePRDM16gene has been associated with human cardiomyopathy. The PRDM16 protein is a transcriptional regulator affecting cardiac development via Tbx5 and Hand1 regulating myocardial structure. BiallelicPrdm16inactivation induces severe cardiac dysfunction with postnatal lethality and hypertrophy in mice. Early pathological events uponPrdm16inactivation have not been explored.MethodsThis study performed in depth pathophysiological and molecular analysis of male and femalePrdm16csp1/wtmice carrying systemic, monoallelicPrdm16gene inactivation. We systematically assessed early molecular changes with transcriptomics, proteomics, and metabolomics. Kinetic modelling of the cardiac metabolism was undertakenin silicowith CARDIOKIN.ResultsPrdm16csp1/wtmice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice.Prdm16csp1/wthearts demonstrate moderate alterations of specific transcripts and protein levels with consistent upregulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre B-cell leukemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional upregulation was detected forPrdm16itself probably by an autoregulatory mechanism.Prdm16csp1/wtcardiac tissue showed reduction of metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and tricarboxylic acid cycle. Global lipid metabolism was also affected with accumulation of triacylglycerides detected in malePrdm16csp1/wthearts. In addition,Prdm16csp1/wtcardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. Metabolic modellingin silicosuggested lowered fatty acid utilization in male and reduced glucose utilization in femalePrdm16csp1/wtcardiac tissue.ConclusionsMonoallelicPrdm16mutation restricts cardiac performance inPrdm16csp1/wtmice. Metabolic alterations precede transcriptional dysregulation inPrdm16csp1/wtcardiac tissue. FemalePrdm16csp1/wtmice develop a more pronounced phenotype indicating a sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event inPRDM16associated cardiac pathology.Novelty and SignificanceWhat Is Known?- Mutation of thePRDM16gene has been associated with human cardiomyopathy.- Biallelic inactivation ofPrdm16in mice induces severe cardiac dysfunction with early postnatal lethality.- Prdm16 cooperates with transcription factors such as Tbx5 and Hand1 to activate transcriptional programs that define the development of the compacted myocardium.What New Information Does This Article Contribute?- Systemic, monoallelic inactivation inPrdm16csp1/wtmice induces cardiac dysfunction with normal survival.- Metabolic alterations are the leading pathophysiological consequences and induce cardiac hypoplasia. On the molecular level this is associated with upregulation of metabolic regulators Pyroxd2 and Pbxip1.- Metabolic response afterPrdm16inactivation occurs in a sex specific manner.