The Transcription Factor TFEB Protects Against Cardiac Hypertrophy by Increasing Lysosomal Capacity and Activating AMPKα

Heart failure is one of the leading causes of morbidity and mortality in the modern world. Stress-induced pathological hypertrophy is observed in most forms of heart disease. Pathological cardiac remodeling is a hallmark of impending heart failure. Lysosome-assisted processes such as autophagy and mitophagy play important roles in this remodeling, as do signaling pathways associated with the lysosome, such as AMPK and mTOR, a negative and positive regulator of hypertrophy, respectively. Yet, lysosomal biogenesis and function remain poorly studied in the heart, and the possible role of the lysosome as a signaling nexus for hypertrophic stress is as yet unknown. Recently, the transcription factor EB (TFEB) has emerged as a key regulator of lysosomal genes in multiple tissues, especially in response to external stress. Here, we set out to test the hypothesis that TFEB-dependent control of lysosomal biogenesis is required in the setting of pathological hypertrophic stress. Our data demonstrate that TFEB is activated and translocates to the nucleus in cardiomyocytes under hypertrophic stress conditions and upregulates lysosomal genes. We engineered a novel cardiomyocyte-specific TFEB knockout mouse (CTKO). At baseline, contractile function measured by echocardiography appears normal in these mice compared to their Cre-negative littermates. However, in the setting of hypertrophic stress, the CTKO mice manifest an exacerbated hypertrophic response leading quickly to heart failure. As expected, we observe a failure in the up-regulation of key TFEB-mediated lysosomal genes after TAC (thoracic aortic constriction) in CTKO mice. In contrast, autophagosome-associated proteins such as LC3II and p62 are increased in the CTKO animals after TAC, as are levels of ubiquitinated proteins, suggesting a decrease in protein turnover. Surprisingly, AMPK signaling is significantly decreased in the CTKO hearts. To further elucidate the cardiomyocyte-specific effects and regulation of TFEB we employed a loss-of-function (knockdown) approach in neonatal rat ventricular myocytes (NRVMs) challenged with pro-hypertrophic stimuli. Our in vitro system phenocopies the exacerbated hypertrophic response seen in vivo. We confirmed a requirement for TFEB in the activation of AMPK signaling under hypertrophic conditions. This occurs in a manner dependent on Camkk2 activity. Based on these data, we conclude that TFEB antagonizes pathological, hypertrophic cardiac remodeling through up-regulation of lysosomal capacity and AMPK signaling. Ins light of recent effort in developing TFEB agonists, our study has potential translational importance.

Author dc:creator

• Das Gupta, Subhajit

Contributors dc:contributor

• Shaul, Philip W.
• Gillette, Thomas G.
• Hill, Joseph A.
• Bickel, Perry
• Wang, Zhao
• Zaha, Vlad G.

• AMP-Activated Protein Kinases
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Cardiomegaly
• Lysosomes

Language dc:language

en

Identifier

1522122343

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10590