An <scp>mTOR</scp> ‐Tfeb‐Fabp7a Axis Ameliorates <i>bag3</i> Cardiomyopathy via Decelerating Cardiac Aging

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.