Abstract P2056: The Transcription Factor TFEB Protects Against Cardiac Hypertrophy By Increasing Lysosomal Capacity And Activating AMPKα

Abstract

Introduction: Pathological cardiac remodeling in response to elevated afterload can eventually progress to heart failure. Lysosome-assisted processes such as autophagy play an important role in this remodeling. The lysosome is also a nexus for some of the same signaling pathways that are involved in hypertrophic growth. The transcription factor EB (TFEB) has emerged as a key regulator of lysosomal genes in multiple tissues, especially in response to external stress. Methods and Results: Here, we report that TFEB is rapidly activated and translocates to the nucleus in cardiomyocytes under hypertrophic stress conditions, activating a lysosomal gene program independent of autophagy gene changes. We engineered a cardiomyocyte-specific TFEB knockout mouse (CTKO). At baseline, contractile function measured by echocardiography appears normal in these mice compared with their Cre-negative littermates. However, in the setting of pressure-overload stress induced by TAC (thoracic aortic constriction), the CTKO mice manifest an exacerbated hypertrophic response leading quickly to heart failure. Unlike the WT hearts, CTKO hearts fail to increase lysosomal capacity after TAC and manifest an increase in steady-state levels of autophagosome-associated proteins such as LC3II and p62, as well as accumulation of ubiquitinated proteins, suggesting a decrease in protein turnover. Surprisingly, AMPK signaling, while normal at baseline is significantly decreased in the CTKO hearts after TAC. This reliance on TFEB for PE-induced AMPK signaling is also observed in vitro , as are the anti-hypertrophic effects of TFEB activation, supporting a direct role of TFEB in this process. Finally, we show that exogenous activation of AMPK in the absence of TFEB can completely rescue the exacerbated hypertrophic response both in vitro and in vivo , independent of lysosomal function. Surprisingly, blunting of the hypertrophic response had no impact on the decreased cardiac function observed in the TAC-treated CTKO mice. Conclusion: Overall, our findings suggest that TFEB antagonizes pathological hypertrophic cardiac remodeling through up-regulation of lysosomal capacity and AMPK signaling.