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| Item Type: | Preprint |
|---|---|
| Title: | Loss of cardiomyocyte eukaryotic elongation factor 1A2 in adult mice triggers cardiomyopathy due to defective proteostasis |
| Creators Name: | Martin-Garrido, Abel, Weyrauch, Nadine, Ruiz-Orera, Jorge, Eresch, Jeanette, Reitter, Sonja, Cordero, Julio, Scheich, Viktoria, Grund, Andrea, Keles, Merve, Weinzierl, Nina, Hofmann, Ellen, Trogisch, Felix A., Hemanna, Shruthi, Stoecklin, Georg, Voelkers, Mirko, Hubner, Norbert, Dobreva, Gergana and Heineke, Joerg |
| Abstract: | The eukaryotic elongation factor 1A (eEF1A) is known for its canonical role to promote the translocation of aminoacyl-tRNAs to ribosomes during translational elongation, but also has non-canonical functions. In mammals, two paralogs of eEF1A exist: Whereas eEF1A1 is ubiquitously expressed, eEF1A2 expression is restricted to adult cardiomyocytes, skeletal myocytes and neurons. Although patients with mutations in EEF1A2 develop cardiomyopathies, the mechanism involved is unknown. To study the role of cardiac eEF1A2 in adult mice, we generated adult induced, cardiomyocyte specific Eef1a2 knock-out (eEF1A2-cKO), and Eef1a1/Eef1a2 double knock-out (eEF1A1/eEF1A2-cKO) mice. eEF1A2-cKO mice developed cardiomyopathy associated with increased mouse mortality, cardiac dysfunction and fibrosis, but unchanged global protein synthesis rates, while eEF1A1/eEF1A2-cKO mice exhibited early sudden death. Combined RNA sequencing, proteomics and ribosomal sequencing analyses from hearts of eEF1A2-cKO and eEF1A1/eEF1A2-cKO mice revealed a post-transcriptional upregulation of ribosomal proteins and translational regulators. On the other hand, we observed an increase of autophagosomes and protein aggregates in heart tissue of eEF1A2-cKO mice as sign of defective autophagy. Mechanistically, we demonstrate that eEF1A2 acts as a chaperone in cardiomyocytes. Finally, administration of rapamycin (mTORC1 inhibitor) at an early disease stage in eEF1A2-cKO mice normalized systolic cardiac dysfunction and mortality and eliminated the accumulation of autophagosomes and protein aggregates. Together, we found that eEF1A2 promotes proteostasis in cardiomyocytes, at least in part by supporting protein folding. More importantly, increased mortality, cardiomyopathy and proteostasis defects due to the lack of eEF1A2 could be rescued by administration of rapamycin, which might therefore constitute a treatment strategy for patients with EEF1A2 mutations. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.01.14.699518 |
| Date: | 15 January 2026 |
| Official Publication: | https://doi.org/10.64898/2026.01.14.699518 |
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