ROLE OF TRANSCRIPTION FACTOR EB (TFEB) IN CARDIAC HEALTH AND DISEASE

Abstract

Cardiomyopathy is prevalent and the leading cause of mortality among obese and diabetic patients. Abnormalities in cardiac energy metabolism trigger myocyte dysfunction that precedes the onset of cardiomyopathy. Lack of insulin function trigger metabolic remodeling rendering cardiomyocytes susceptible to detrimental effects of hyperglycemia and fatty acid (FA) overutilization. Glucolipotoxicity precipitate ER stress, mitochondrial dysfunction, impairment in Ca2+-handling and protein degradation, leading to myocyte injury and death. Using in-vivo and ex-vivo models, data from my doctoral thesis demonstrated that glucolipotoxicity impairs protein degradation pathway of lysosomal autophagy, causing cardiomyocyte injury. Gene expression of lysosomal proteins governing lysosomal metabolism and proteolytic (autophagy) function are under the direct control of transcription factor EB (TFEB), belonging to the microphthalmia/TFE family. My data show that glucolipotoxicity following nutrient-overload causes cardiomyocyte injury by inhibiting TFEB and suppressing lysosomal function. I next ascertained if types of FA and duration of FA exposure regulate TFEB action and dictate cardiomyocyte viability. Saturated FA, palmitate, but not polyunsaturated FAs, decreased TFEB content in a concentration- and time-dependent manner in cardiomyocytes. Hearts from high-fat high-sucrose diet-fed mice showed a temporal decline in nuclear TFEB content with a marked elevation of distinct lipid species suggesting that myocyte lipid loading and loss of TFEB are concomitant molecular events. To identity signaling and metabolic pathways modulated by the loss of TFEB action in cardiomyocytes transcriptome analysis in murine cardiomyocytes with targeted deletion of TFEB (TFEB-/-) was conducted. RNA-sequencing analysis revealed enrichment of differentially expressed genes (DEGs) representing pathways of nutrient metabolism, cell death/apoptosis and cardiac function. Transcriptome analysis also showed upregulation of genes involved in lipid biosynthesis and storage, whereas genes associated with lipid catabolism were downregulated in myocyte with TFEB deletion. TFEB-/- cardiomyofibroblasts exhibited higher lipid droplet accumulation and increased caspase-3 activation, whereas constitutive activation of TFEB abrogated the phenotype. Notably, electrically stimulated TFEB-/- cardiomyocytes displayed an increase in Ca2+ transient amplitude. Together, our data demonstrated that TFEB plausibly regulates non-canonical energy metabolism pathways other than the canonical pathway of autophagy in cardiomyocytes. Loss of TFEB function in cardiomyocytes remodels energy metabolism and renders cardiomyocyte susceptible to nutrient-overload-induced injury. Probing intramyocellular mechanisms regulating TFEB and identifying pathways targeted by TFEB offers promising therapeutic options for treating patients with metabolic heart failure.