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| Item Type: | Preprint |
|---|---|
| Title: | Loss of cardiomyocyte eukaryotic elongation factor 1A2 in mice triggers cardiomyopathy due to defective proteostasis |
| Creators Name: | Martin-Garrido, Abel, Weyrauch, Nadine, Ruiz-Orera, Jorge, Eresch, Jeanette, Reitter, Sonja, Cordero, Julio, Senger, Frauke, Scheich, Viktoria, Grund, Andrea, Keles, Merve, Weinzierl, Nina, Hofmann, Ellen, Trogisch, Felix A., Hemanna, Shruthi, Buettner, Michael, Poschet, Gernot, Rettel, Mandy, Stein, Frank, Rog-Zielinska, Eva A., Frey, Norbert, Stoecklin, Georg, Voelkers, Mirko, Hubner, Norbert, Dobreva, Gergana and Heineke, Joerg |
| Abstract: | Eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl-tRNAs to ribosomes but also has additional, non-canonical functions. Mammals express two paralogs: eEF1A1 is ubiquitous, whereas eEF1A2 is confined to adult cardiomyocytes, skeletal myocytes, and neurons. Mutations in EEF1A2 cause cardiomyopathy, but underlying mechanisms remain unclear. Using adult, cardiomyocyte-specific Eef1a2 knock-out (Eef1a2-cKO) and Eef1a1/Eef1a2 double knock-out mice, we show that Eef1a2-cKO animals develop cardiomyopathy with increased mortality, systolic dysfunction, and fibrosis, despite unchanged global protein synthesis, while double knock-out mice die early in a sudden manner. Multi-omics analyses reveal post-transcriptional upregulation of ribosomal proteins and translational regulators in both models. Eef1a2-cKO hearts accumulate autophagosomes and protein aggregates, indicating defective autophagy. Mechanistically, we found that eEF1A2 functions as a chaperone supporting protein folding and proteostasis in cardiomyocytes. Early Rapamycin treatment (mTORC1 inhibition) normalizes systolic heart function and survival in Eef1a2-cKO mice and clears autophagosomes and protein aggregates. Thus, eEF1A2 maintains cardiac proteostasis, and mTORC1 inhibition may represent a therapeutic strategy for patients with EEF1A2 mutations. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.01.14.699518v2 |
| Date: | 18 February 2026 |
| Official Publication: | https://doi.org/10.64898/2026.01.14.699518 |
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