Whole heart RNA sequencing was performed prior to the onset of cardiac dysfunction in the Lmna-/- and matched control mice. Differentially expressed transcripts and their upstream regulators were identified, validated, and targeted by AAV9-shRNA constructs. A total of 576 transcripts were upregulated and 233 were downregulated in the Lmna-/- mouse hearts (q<0.05). FOXO transcription factors (TFs) were the most activated, while E2Fs were the most suppressed transcriptional regulators. Transcript levels of FOXO targets were also upregulated in the isolated Lmna-/- cardiac myocytes and in the myocardium of human heart failure patients. Nuclear localization of FOXO1 and 3 was increased, whereas phosphorylated (inactive) FOXO1 and 3 levels were reduced in the Lmna-/- hearts. Gene Set Enrichment Analysis and Gene Ontology showed activation of apoptosis and inflammation and suppression of cell cycle, adipogenesis, and oxidative phosphorylation in the Lmna-/- hearts. AAV9-shRNA-mediated suppression of FOXO TFs rescued selected molecular signatures, improved apoptosis, and prolonged survival by ~2-fold. Conclusions: FOXO TFs are activated and contribute to the pathogenesis of cardiac phenotype in laminopathies. Suppression of the FOXO TFs in cardiac myocytes partially rescues the phenotype and prolongs survival. The findings identify FOXO TFs as potential therapeutic targets for cardiac phenotype in laminopathies. Read more »