The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB

Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) play fundamental role in regulation of cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy in cardiomyocytes. Here, we characterized a mechanism by which ERRs induce autophagy in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be important in cardiac autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C 2 C 12 myoblasts. ERR-dependent increases in TFEB expression results in increased expression of an array of TFEB target genes, which are critical for stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for treatment of many diseases where stimulation of autophagy may be therapeutic including heart failure.