Biology subjects

Weinzierl, N.

Publications and source records attributed to Weinzierl, N..

3 recordsLinked to original sources

bioRxiv2026

Loss of cardiomyocyte eukaryotic elongation factor 1 A2 in adult mice triggers cardiomyopathy due to defective proteostasis

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.

physiology↗

bioRxiv2024

Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia

Cancer cachexia, a multifactorial condition resulting in muscle and adipose tissue wasting, reduces the quality of life of many people with cancer. Despite decades of research, therapeutic options for cancer cachexia remain limited. Cachexia is highly prevalent in people with pancreatic ductal adenocarcinoma (PDAC), and many animal models of pancreatic cancer are used to understand mechanisms underlying cachexia. One such model is the KrasLSL-G12D, Ptf1aCre-ER/+, Ptenflox/flox (KPP) model, which utilizes an inducible Cre recombinase to allow tumor development to be initiated at any age by tamoxifen administration. In our previous work, tumors were induced in KPP mice at 4 weeks of age. However, mice are still rapidly growing at this age, and a portion of the body weight differences seen between control and KPP mice is likely due to slowed growth of KPP mice. In our current study, pancreatic tumors were induced to develop with tamoxifen in KPP mice after rapid postnatal growth has slowed at 10 weeks of age (KPP10). Similar to our previous findings, KPP10 mice had lower body, muscle, and adipose tissue weights compared to non-tumor mice, and these differences were similar between male and female mice. However, male mice experienced greater relative weight loss. Unexpectedly, we identified that overall survival was significantly shorter in female KPP10 mice compared to KPP10 males. Greater body weight at tumor induction was associated with longer survival, suggesting that the sex difference in survival may be related to differences in body weight between male and female mice. NEW & NOTEWORTHY- Although male mice experience greater relative body weight losses, similar skeletal muscle and adipose tissue wasting occurs between male and female mice in the KrasLSL-G12D, Ptf1aCre-ER/+, Ptenflox/flox (KPP) model of pancreatic-cancer induced cachexia. - Greater weight loss in males may be related to longer survival. However, differences in tamoxifen dose relative to body weight may have accelerated tumor formation in female mice and therefore may be a relevant consideration for inducible tumor models.

physiology↗

bioRxiv2022

Secreted long non-coding RNAs Gadlor1 and Gadlor2 affect multiple cardiac cell types and aggravate cardiac remodeling during pressure overload

BackgroundPathological overload triggers maladaptive myocardial remodeling that leads to heart failure. Recent studies have shown that long non-coding RNAs (lncRNAs) regulate cardiac remodeling. This study investigates two recently discovered, secreted lncRNAs, Gadlor1 and Gadlor2 (Gadlor 1/2). MethodsWe generated compound Gadlor1/2 knock-out (KO) mice and compared their response to pressure overload by transverse aortic constriction (TAC) to that of wild-type (WT) littermates. Endothelial cells, fibroblasts and cardiomyocytes were isolated from the hearts of both genotypes after TAC and their transcriptome was investigated by RNA sequencing. Gadlor target proteins were identified by RNA antisense purification coupled with mass spectrometry (RAP-MS) in cardiomyocytes. In addition, we investigated the effects of cardiac overexpression of Gadlor1/2. ResultsGadlor1/2 are jointly upregulated in failing mouse hearts as well as in the myocardium of heart failure patients. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 KO mice, in turn, exerted markedly reduced myocardial hypertrophy, fibrosis and dysfunction, but more angiogenesis during short and long-standing pressure overload. Paradoxically, Gadlor1/2 KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene-expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, induce pro-hypertrophic gene-expression and enhance calcium re-uptake into the sarcoplasmic reticulum. ConclusionGadlor1 and Gadlor2 are lncRNAs that are mainly enriched in EC-derived EVs and are jointly upregulated in mouse and human hearts during pathological overload. We reveal a crucial endothelial cell-cardiomyocyte crosstalk, which aims at restoring calcium homeostasis in cardiomyocytes during overload at the cost of aggravated hypertrophy and fibrosis.

systems biology↗