An mTOR-Tfeb-Fabp7a signaling axis can be harnessed to ameliorate cardiomyopathy in adult zebrafish.

Dysregulated proteostasis in cardiomyocytes is an important pathological event in cardiomyopathy, which can be repaired by inhibiting mechanistic target of rapamycin (mTOR) for cardioprotective effects. Here, we aimed to uncover additional pathological events and therapeutic target genes via leveraging zebrafish genetics. We first assessed transcription factor EB ( ), a candidate gene that encodes a direct downstream phosphorylation target of mTOR signaling. We found that cardiomyocyte-specific transgenic overexpression of ( ) is sufficient to repair defective proteostasis, attenuate accelerated cardiac senescence, a previously unrecognized phenotype in the cardiomyopathy model, and rescue cardiac dysfunction. Next, we compared cardiac transcriptomes between the transgenic fish and the mutant, and tested 4 commonly downregulated lipodystrophy genes using an F0-based genetic assay. We found that inhibition of the fatty acid binding protein a ( ) gene, but not the other 3 genes, exerts therapeutic effects on cardiomyopathy. Conversely, expression is elevated in cardiomyopathy model and cardiomyocyte-specific overexpression of resulted in dysregulated proteostasis, accelerated cardiac senescence, as well as cardiac dysfunction. Together, these genetic studies in zebrafish uncovered Fabp7a activation and accelerated cardiac senescence as important pathological events in cardiomyopathy. The mTOR-Tfeb-Fabp7a signaling axis can be harnessed to repair these pathological changes and exert cardioprotective effects.