TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux.

Abstract

Insufficient lysosomal removal of autophagic cargoes in cardiomyocytes has been suggested as a main cause for the impairment of the autophagic-lysosomal pathway (ALP) in many forms of heart disease including cardiac proteinopathy and may play an important pathogenic role; however, the molecular basis and the correcting strategy for the cardiac ALP insufficiency require further investigation. The present study was sought to determine whether myocardial expression and activity of TFEB, the recently identified ALP master regulator, are impaired in a cardiac proteinopathy mouse model and to determine the effect of genetic manipulation of TFEB expression on autophagy and proteotoxicity in a cardiomyocyte model of proteinopathy. We found that increased myocardial TFEB mRNA levels and a TFEB protein isoform switch were associated with marked decreases in the mRNA levels of representative TFEB target genes and increased mTORC1 activation, in mice with cardiac transgenic expression of a missense (R120G) mutant αB-crystallin (CryABR120G), a well-established model of cardiac proteinopathy. Using neonatal rat ventricular cardiomyocyte cultures, we demonstrated that downregulation of TFEB decreased autophagic flux in cardiomyocytes both at baseline and during CryABR120G overexpression and increased CryABR120G protein aggregates. Conversely, forced TFEB overexpression increased autophagic flux and remarkably attenuated the CryABR120G overexpression-induced accumulation of ubiquitinated proteins, caspase 3 cleavage, LDH leakage, and decreases in cell viability. Moreover, these protective effects of TFEB were dramatically diminished by inhibiting autophagy. We conclude that myocardial TFEB signaling is impaired in cardiac proteinopathy and forced TFEB overexpression protects against proteotoxicity in cardiomyocytes through improving ALP activity.

• Authors: Bo Pan, Hanming Zhang, Taixing Cui, Xuejun Wang
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 113 Pg. 51-62 (12 2017) ISSN: 1095-8584 [Electronic] England
• PMID: 28993153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• RNA, Messenger
• alpha-Crystallin B Chain
• Mechanistic Target of Rapamycin Complex 1

Topics

• Animals
• Autophagy (physiology)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Cell Survival (physiology)
• Female
• Heart Diseases (metabolism)
• Heart Ventricles (metabolism)
• Lysosomes (metabolism)
• Male
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (physiology)
• alpha-Crystallin B Chain (metabolism)