PUBLICATION
An mTOR-Tfeb-Fabp7a Axis Ameliorates bag3 Cardiomyopathy via Decelerating Cardiac Aging
- Authors
- Ding, Y., Ma, X., Yan, F., Yoon, B., Wei, W., Zhang, Y., Lin, X., Xu, X.
- ID
- ZDB-PUB-250909-15
- Date
- 2025
- Source
- Aging Cell : e70216e70216 (Journal)
- Registered Authors
- Ding, Yonghe, Lin, Xueying, Xu, Xiaolei
- Keywords
- none
- MeSH Terms
-
- Animals, Genetically Modified
- Cardiomyopathies*/genetics
- Cardiomyopathies*/metabolism
- Cardiomyopathies*/pathology
- Signal Transduction
- TOR Serine-Threonine Kinases*/genetics
- TOR Serine-Threonine Kinases*/metabolism
- Adaptor Proteins, Signal Transducing*/genetics
- Adaptor Proteins, Signal Transducing*/metabolism
- Fatty Acid-Binding Proteins*/genetics
- Fatty Acid-Binding Proteins*/metabolism
- Humans
- Zebrafish
- Disease Models, Animal
- Aging*/metabolism
- Apoptosis Regulatory Proteins*/genetics
- Apoptosis Regulatory Proteins*/metabolism
- Myocytes, Cardiac/metabolism
- Animals
- PubMed
- 40922543 Full text @ Aging Cell
Citation
Ding, Y., Ma, X., Yan, F., Yoon, B., Wei, W., Zhang, Y., Lin, X., Xu, X. (2025) An mTOR-Tfeb-Fabp7a Axis Ameliorates bag3 Cardiomyopathy via Decelerating Cardiac Aging. Aging Cell. :e70216e70216.
Abstract
While BAG3 has been identified as a causative gene for dilated cardiomyopathy, the major pathological events in BAG3-related cardiomyopathy that could be targeted for therapeutic benefit remain to be discovered. Here, we aim to uncover novel pathological events through genetic studies in a zebrafish bag3 cardiomyopathy model. Given the known cardioprotective effects of mtor inhibition and the fact that transcription factor EB (tfeb) encodes a direct downstream phosphorylation target of mTOR signaling, we generated a cardiomyocyte-specific transgenic line overexpressing tfeb (Tg[cmlc2:tfeb]). This overexpression was sufficient to restore defective proteostasis and rescue cardiac dysfunction in the bag3 cardiomyopathy model. Importantly, we detected accelerated cardiac senescence in the bag3 cardiomyopathy model, which can be mitigated by Tg(cmlc2:tfeb). We compared cardiac transcriptomes between the Tg(cmlc2:tfeb) transgenic fish and the mtorxu015/+ mutant and found that inhibition of the fatty acid binding protein a (fabp7a) gene exerts therapeutic effects. Consistent with this genetic evidence, we detected elevated fabp7a expression in the bag3 cardiomyopathy model, whereas cardiomyocyte-specific overexpression of fabp7a induced dysregulated proteostasis, accelerated cardiac senescence, and cardiac dysfunction. To elucidate the functions of Fabp7a in normative cardiac aging, we turned to the African Turquoise Killifish. We noted elevated Fabp7a expression in the hearts of aged killifish, and pharmacological inhibition of Fabp7a mitigated the cardiac aging process. Together, this study uncovered accelerated cardiac senescence as a key pathological event in bag3 cardiomyopathy and reveals that manipulating the mTOR-Tfeb-Fabp7a axis can mitigate this pathology and confer cardioprotective effects.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping