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Transcription Factor EB Activation Rescues Advanced αB-Crystallin Mutation-Induced Cardiomyopathy by Normalizing Desmin Localization. J Am Heart Assoc 2019 02 19;8(4):e010866



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Scopus ID

2-s2.0-85061707716   13 Citations


Background Mutations in αB-crystallin result in proteotoxic cardiomyopathy with desmin mislocalization to protein aggregates. Intermittent fasting ( IF ) is a novel approach to activate transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in the myocardium. We tested whether TFEB activation can be harnessed to treat advanced proteotoxic cardiomyopathy. Methods and Results Mice overexpressing the R120G mutant of αB-crystallin in cardiomyocytes ( Myh6-Cry ABR 120G) were subjected to IF or ad-lib feeding, or transduced with adeno-associated virus- TFEB or adeno-associated virus-green fluorescent protein after development of advanced proteotoxic cardiomyopathy. Adeno-associated virus-short hairpin RNA-mediated knockdown of TFEB and HSPB 8 was performed simultaneously with IF . Myh6-Cry ABR 120G mice demonstrated impaired autophagic flux, reduced lysosome abundance, and mammalian target of rapamycin activation in the myocardium. IF resulted in mammalian target of rapamycin inhibition and nuclear translocation of TFEB with restored lysosome abundance and autophagic flux; and reduced aggregates with normalized desmin localization. IF also attenuated left ventricular dilation and myocardial hypertrophy, increased percentage fractional shortening, and increased survival. Adeno-associated virus- TFEB transduction was sufficient to rescue cardiomyopathic manifestations, and resulted in reduced aggregates and normalized desmin localization in Myh6-Cry ABR 120G mice. Cry ABR 120G-expressing hearts demonstrated increased interaction of desmin with αB-crystallin and reduced interaction with chaperone protein, HSPB 8, compared with wild type, which was reversed by both IF and TFEB transduction. TFEB stimulated autophagic flux to remove protein aggregates and transcriptionally upregulated HSPB 8, to restore normal desmin localization in Cry ABR 120G-expressing cardiomyocytes. Short hairpin RNA-mediated knockdown of TFEB and HSPB 8 abrogated IF effects, in vivo. Conclusions IF and TFEB activation are clinically relevant therapeutic strategies to rescue advanced R120G αB-crystallin mutant-induced cardiomyopathy by normalizing desmin localization via autophagy-dependent and autophagy-independent mechanisms.

Author List

Ma X, Mani K, Liu H, Kovacs A, Murphy JT, Foroughi L, French BA, Weinheimer CJ, Kraja A, Benjamin IJ, Hill JA, Javaheri A, Diwan A


Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
DNA Mutational Analysis
DNA, Mitochondrial
Disease Models, Animal
Mice, Transgenic
Microscopy, Electron, Transmission
Myocytes, Cardiac
alpha-Crystallin B Chain
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a