PUBLICATION
Deregulated nutrient response in ttntv cardiomyopathy can be repaired via Erk inhibition for cardioprotective effects
- Authors
- Yan, F., Wang, W., Moossavi, M., Zhu, P., Odell, N., Xu, X.
- ID
- ZDB-PUB-250714-6
- Date
- 2025
- Source
- Journal of Molecular and Cellular Cardiology : (Journal)
- Registered Authors
- Xu, Xiaolei, Zhu, Ping
- Keywords
- Dilated cardiomyopathy, ERK, TTNtv, Nutrient response, Zebrafish
- MeSH Terms
-
- Cardiotonic Agents*/pharmacology
- Humans
- Zebrafish/genetics
- Animals
- MAP Kinase Signaling System*/drug effects
- Cardiomyopathies*/genetics
- Cardiomyopathies*/metabolism
- Connectin*/genetics
- Cardiomyopathy, Dilated*/genetics
- Cardiomyopathy, Dilated*/metabolism
- Disease Models, Animal
- PubMed
- 40653307 Full text @ J. Mol. Cell. Cardiol.
Citation
Yan, F., Wang, W., Moossavi, M., Zhu, P., Odell, N., Xu, X. (2025) Deregulated nutrient response in ttntv cardiomyopathy can be repaired via Erk inhibition for cardioprotective effects. Journal of Molecular and Cellular Cardiology. :.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping