# An mTOR‐Tfeb‐Fabp7a Axis Ameliorates bag3 Cardiomyopathy via Decelerating Cardiac Aging

## TL;DR

This study identifies a new pathway involving mTOR, Tfeb, and Fabp7a that can reduce heart damage in a zebrafish model of BAG3-related cardiomyopathy by slowing cardiac aging.

## Contribution

The study reveals a novel mTOR-Tfeb-Fabp7a pathway that ameliorates BAG3 cardiomyopathy by targeting accelerated cardiac senescence.

## Key findings

- Overexpression of Tfeb rescues cardiac dysfunction and proteostasis defects in the bag3 cardiomyopathy model.
- Elevated Fabp7a expression contributes to cardiac aging and dysfunction, which can be mitigated by its inhibition.
- Pharmacological inhibition of Fabp7a reduces cardiac aging in African Turquoise Killifish.

## 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 mtor

xu015/+
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.

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.