An mTOR-Tfeb-Fabp7a Axis Ameliorates bag3 Cardiomyopathy via Decelerating Cardiac Aging.

Yonghe Ding, Xueling Ma, Feixiang Yan, Baul Yoon, Wei Wei, Yuji Zhang, Xueying Lin, Xiaolei Xu

Department of Biochemistry and Molecular Biology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA. · pubmed

Paper

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

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Research summary

The paper claims that overexpression of tfeb can restore proteostasis and mitigate cardiac senescence in a bag3 cardiomyopathy model. This research is relevant as it explores mechanisms that could potentially target the aging process in cardiac tissue, addressing root causes of age-related cardiac dysfunction rather than merely treating symptoms.

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