Constitutive expression of cardiomyocyte Klf9 precipitates metabolic dysfunction and spontaneous cardiomyopathy

Adaptation of gene expression is the earliest response during work overload to maintain cardiac homeostasis and function. We reported a novel function of Krüppel-like factor (Klf) 9 in mediating metabolic adaptations in response to Dexamethasone in cardiomyocytes. Klf9 expression decreases in hearts undergoing cardiac hypertrophy and failure, suggesting that differential regulation of Klf9 could be contributing to the pathogenesis. Here, we present the characterization of a conditional (αMHC-Cre) Klf9 knock-in (Klf9KI) mouse. Constitutive expression of exogenous Klf9 results in spontaneous cardiac dysfunction and the onset of failure by 8 weeks of age, and an early mortality by 12-14 weeks, suggesting that Klf9 dysregulation is sufficient for maladaptation. Transcriptome data from 1-week-old Klf9KI hearts show dysregulation of genes involved in lipid, carbohydrate, and glutathione metabolism, and transcripts of transport, transcription, and motor proteins. At 4 weeks and 8 weeks, we observe a differential expression of genes involved in innate immunity and extracellular matrix, along with metabolic and contractile signaling. These data correlate with the untargeted metabolome analysis, showing dysregulation in metabolites of lipid and fatty acids, glutathione, purine and pyrimidines, and sucrose metabolic pathways. Functional data in Klf9KI hearts show a decrease in mitochondrial ETC complex activity and ATP production, and an increase in ROS. Structural mitochondrial defects include distortion and sparse cristae in Klf9KI vs. Wt-Cre hearts. In conclusion, we show that Klf9 is critical for metabolic adaptations in postnatal heart development. Constitutive expression of Klf9 results in metabolic maladaptation, which precipitates dysfunction, early onset of heart failure, and death.