Deregulated nutrient response in ttntv cardiomyopathy can be repaired via Erk inhibition for cardioprotective effects

Background

Truncating TITIN variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM); however, key pathological signaling pathways remain elusive. We recently established a zebrafish model of TTNtv DCM and developed a F0-based genome editing technology for the rapid screening of genetic modifiers.

Methods

We screened multiple known cardiomyopathy signaling pathways through a F0-based genetic assay using a zebrafish ttntv DCM model. Because ERK signaling was identified from the screen, which was also independently identified as an altered signaling pathway during a cardiac transcriptomic study of the ttntv DCM model, we then assessed modifying effects of differentially expressed genes (DEGs) in ERK signaling.

Results

erk1 and mek1 have been identified as therapeutic modifiers for ttntv DCM. Consistent with their modifying effects, we observed increased levels of phosphorylated Erk1 protein in ttntv adult zebrafish. Mechanistically, we showed that enhanced ERK signaling results in deregulated nutrient response, as indicated by the muted response of phosphorylated ribosomal protein S6 (pS6) expression in the heart during the fasting-refeeding cycle. The inhibition of ERK signaling is sufficient to rescue deregulated nutrient response and mitigate cardiac dysfunction. Further genetic screens of DEGs in ERK signaling identified ppp1r10, encoding a protein phosphatase 1 (PP1) regulatory subunit that regulates Mek1/Erk1 phosphorylation, as another therapeutic modifier gene that also rescues deregulated nutrient response.

Conclusions

An Erk - nutrient response signaling axis is disrupted in ttntv cardiomyopathy, which can be repaired by the inhibition of erk1, mek1 or ppp1r10, suggesting a new therapeutic avenue for TTNtv DCM.