TIGAR DEFICIENCY ENHANCES CARDIAC RESILIENCE THROUGH EPIGENETIC PROGRAMMING OF PARKIN EXPRESSION

ABSTRACT BACKGROUND While mitochondrial dysfunction clearly drives cardiac deterioration in major heart diseases, the mechanisms controlling mitochondrial quality remain incompletely understood. This study investigated whether TIGAR (TP53-induced glycolysis and apoptosis regulator) deficiency influences cardiac protection through mitochondrial quality control pathways. METHODS We generated both whole-body and cardiomyocyte-specific TIGAR knockout mice that were assessed for cardiac function following myocardial infarction (induced by left anterior descending coronary artery ligation) and diet-induced cardiomyopathy (using a 6-month high-fat diet protocol). Mitochondrial quality control was evaluated through mitophagy assays, subcellular fractionation, and molecular analyses. Epigenetic regulation was assessed using whole-genome bisulfite sequencing, chromatin immunoprecipitation, and CRISPR-mediated gene editing in multiple cell lines. RESULTS Both whole-body (TKO) and cardiomyocyte-specific (hTKO) TIGAR knockout mice demonstrated cardioprotection following myocardial infarction. These animals maintained significantly better ejection fraction (43.35±17.76% vs 26.36±9.83% in wild-type controls, P<0.05) and displayed complete resistance to diet-induced cardiac hypertrophy, despite comparable weight gain. TIGAR deficiency led to dramatic increases in Parkin expression across multiple tissues, 6-fold increases in heart and muscle, and 5-fold increases in brain, which enhanced mitophagic responses during metabolic stress conditions including fasting and high-fat diet feeding. Generation of Parkin/TIGAR double knockout mice eliminated this protection, confirming Parkin’s essential role. Notably, adult manipulation of TIGAR through viral overexpression or knockdown failed to alter Parkin levels, suggesting developmental programming. Whole-genome bisulfite sequencing revealed reduced DNA methylation in a specific 3.2 kb region within Parkin gene intron 10, and CRISPR deletion of this regulatory region increased Parkin expression 10-fold in C2C12 myoblasts and 6-fold in 3T3-L1 fibroblasts. CONCLUSIONS These findings reveal a novel TIGAR-Parkin regulatory axis operating through epigenetic mechanisms during cardiac development to establish lifelong cardioprotection via enhanced mitochondrial quality control. This discovery points toward new therapeutic approaches targeting developmental metabolic programming for heart disease prevention and identifies specific epigenetic targets for cardiovascular therapy. CLINICAL PERSPECTIVE What Is New? TIGAR deficiency establishes lifelong cardiac protection through developmental epigenetic programming of Parkin expression. A novel 3.2 kb differentially methylated region in Parkin intron 10 regulates mitochondrial quality control in the heart. Early metabolic programming during cardiac development can establish permanent cardioprotective phenotypes. The TIGAR-Parkin axis provides protection against both acute ischemic injury and chronic metabolic cardiomyopathy. What Are the Clinical Implications? Targeting the TIGAR-Parkin pathway could provide novel therapeutic approaches for preventing both ischemic heart disease and diabetic cardiomyopathy. Early developmental interventions targeting cardiac metabolism might establish lifelong cardiovascular protection. Epigenetic modifications of mitochondrial quality control genes represent potential therapeutic targets. The findings suggest optimal timing for cardiovascular preventive interventions may be during critical developmental windows.