Intermittent Fasting Reverses an Advanced Form of Cardiomyopathy

Autor: Daniela Zablocki, Risa Mukai, Junichi Sadoshima
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
autophagy
medicine.medical_specialty
DNA Mutational Analysis
Cardiomyopathy
Mice
Transgenic
030204 cardiovascular system & hematology
DNA
Mitochondrial
Desmin
Mice
03 medical and health sciences
0302 clinical medicine
Microscopy
Electron
Transmission
Internal medicine
Intermittent fasting
medicine
Animals
Myocytes
Cardiac
desmin‐related cardiomyopathy
ComputingMilieux_MISCELLANEOUS
intermittent fasting
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
business.industry
Autophagy
Editorials
alpha-Crystallin B Chain
medicine.disease
Disease Models
Animal
Editorial
030104 developmental biology
Endocrinology
Mutation
transcription factor EB
TFEB
Female
heat shock protein B8
Cardiomyopathies
Cardiology and Cardiovascular Medicine
business
protein quality control mechanism
Cell Signalling/Signal Transduction
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
DOI: 10.1161/jaha.118.011863
Popis: 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.
Databáze: OpenAIRE
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