Biology subjects

von Toerne, C.

Publications and source records attributed to von Toerne, C..

7 recordsLinked to original sources

bioRxiv2026

Integrated histological and proteomic mapping of pancreatic adaptations during porcine pregnancy

Pregnancy is a period of extensive metabolic rewiring. Insulin secreting {beta}-cells respond to the metabolic challenges of pregnancy by increasing their mass and size and by altering secretory patterns to maintain glucose homeostasis. If glucose metabolism is not tightly controlled, gestational diabetes may develop. Most studies on {beta}-cell adaptation during pregnancy are derived from rodent models, making translation to the vastly different human gestational setting challenging. In this work, we performed an extensive characterization of pancreatic adaptations throughout porcine pregnancy. Pigs have a long gestational period (114 days) and share a similar size and metabolism to humans, making them an ideal model to bridge the knowledge gap between rodents and humans. By analyzing pancreatic samples from early and late gestational ages, we captured the full trajectory of endocrine remodeling. We observed pregnancy-driven remodeling of endocrine cell types, marked by preferential expansion of pancreatic polypeptide-secreting cells. Proteomic characterization of the pancreas from early and late gestation showed a downregulation of SLC20A2 and ZCCHC7, identifying new protein targets involved in physiological endocrine cell adaptation. Overall, our comprehensive characterization of pancreatic adaptations in the pig model helps bridge the translational gap between rodents and humans and highlights previously unrecognized proteins with therapeutic potential for gestational diabetes.

developmental biology↗

bioRxiv2024

Sexual dimorphism in molecular profiles of resting human skeletal muscle and the response to acute exercise and endurance training

Biological sex has a strong impact on skeletal muscle metabolism and performance. By a comprehensive investigation of epigenetic, transcriptomic and proteomic differences between female and male skeletal muscle of untrained subjects we provide a molecular basis for the sexual dimorphism of glucose and lipid metabolism. The sex-specific multi-OMICs profiles indicate higher degree of glucose turnover and higher abundance of fast-twitch fibers in males and high degree of lipid handling in females. Eight-week endurance training equalized initial differences toward an endurance-trained proteomic profile in both sexes. The untrained muscle of females was more resistant to an acute exercise challenge since stress-responsive transcripts were predominantly upregulated in males. In myotubes from the same donors, transcriptomic differences were hardly conserved, but could be partially restored by treatment with sex hormones. In conclusion, after only 8 weeks training mitigates deeply rooted sex-specific molecular profiles in skeletal muscle toward a common metabolically beneficial response.

biochemistry↗

bioRxiv2023

Engineering of human myotubes toward a mature metabolic and contractile phenotype

1.Skeletal muscle mediates the beneficial effects of exercise, thereby improving insulin sensitivity and reducing the risk for type 2 diabetes. Current human skeletal muscle models in vitro are incapable of fully recapitulating its physiological functions especially muscle contractility. By supplementation of insulin-like growth factor 1 (IGF1), a growth factor secreted by myofibers in vivo, we aimed to overcome these limitations. We monitored the differentiation process starting from primary human CD56-positive myoblasts in the presence/absence of IGF1 in serum-free medium in daily collected samples for 10 days. IGF1-supported differentiation formed thicker multinucleated myotubes showing physiological contraction upon electrical pulse stimulation following day 6. Myotubes without IGF1 were almost incapable of contraction. IGF1-treatment shifted the proteome toward skeletal muscle-specific proteins that contribute to myofibril and sarcomere assembly, striated muscle contraction, and ATP production. Elevated PPARGC1A, MYH7 and reduced MYH1/2 suggest a more oxidative phenotype further demonstrated by higher abundance of proteins of the respiratory chain and elevated mitochondrial respiration. IGF1-treatment also upregulated GLUT4 and increased insulin-dependent glucose uptake compared to myotubes differentiated without IGF1. To conclude, utilizing IGF1, we engineered human myotubes that recapitulate the physiological traits of skeletal muscle in vivo superior to established protocols and overcome limitations of previous standards. This novel "easy to use" model enables investigation of exercise on a molecular level. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/544344v3_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@be17b5org.highwire.dtl.DTLVardef@6a2d2org.highwire.dtl.DTLVardef@1abbd52org.highwire.dtl.DTLVardef@1a721f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Multi-platforms approach for plasma proteomics: complementarity of Olink PEA technology to mass spectrometry-based protein profiling

The plasma proteome is the ultimate target for biomarker discovery. It stores an endless amount of information on the pathophysiological status of a living organism, which is however still difficult to comprehensively access. The high structural complexity of the plasma proteome can be addressed by either a system-wide and unbiased tool such as mass spectrometry (LC-MS/MS) or a highly sensitive targeted immunoassay such as the Proximity Extension Assays (PEA). In order to address relevant differences and important shared characteristics, we tested the performance of LC-MS/MS in data-dependent and -independent acquisition modes and PEA Olink to measure circulating plasma proteins in 173 human plasma samples from a Southern German population-based cohort. We demonstrated the measurement of more than 300 proteins with both LC-MS/MS approaches applied, mainly including high abundance plasma proteins. By the use of the PEA technology, we measured 728 plasma proteins, covering a broad dynamic range with high sensitivity down to pg/ml concentrations. In a next step, we quantified 35 overlapping proteins with all three analytical platforms, verifying the reproducibility of data distributions, measurement correlation and gender-based differential expression. Our work highlights the limitations and the advantages of both, targeted and untargeted approaches, and prove their complementary strengths. We demonstrated a significant gain in proteome coverage depth and subsequent biological insight by platforms combination - a promising approach for future biomarker and mechanistic studies.

biochemistry↗

bioRxiv2020

Adaptive mitochondrial regulation of the proteasome

The proteasome is the main proteolytic system for targeted protein degradation in the cell. Its function is fine-tuned according to cellular needs. Regulation of proteasome function by mitochondrial metabolism, however, is unknown. Here, we demonstrate that mitochondrial dysfunction reduces the assembly and activity of the 26S proteasome in the absence of oxidative stress. Impaired respiratory complex I function leads to metabolic reprogramming of the Krebs cycle and deficiency in aspartate. Aspartate supplementation activates assembly and activity of 26S proteasomes via transcriptional activation of the proteasome assembly factors p28 and Rpn6. This metabolic adaptation of 26S proteasome function involves sensing of aspartate via the mTORC1 pathway. Metformin treatment of primary human cells similarly reduced assembly and activity of 26S proteasome complexes, which was fully reversible and rescued by supplementation of aspartate or pyruvate. Of note, respiratory dysfunction conferred resistance towards the proteasome inhibitor Bortezomib. Our study uncovers a fundamental novel mechanism of how mitochondrial metabolism adaptively adjusts protein degradation by the proteasome. It thus unravels unexpected consequences of defective mitochondrial metabolism in disease or drug-targeted mitochondrial reprogramming for proteasomal protein degradation in the cell. As metabolic inhibition of proteasome function can be alleviated by treatment with aspartate or pyruvate, our results also have therapeutic implications.

cell biology↗

bioRxiv2020

Molecular classification of the placebo effect in nausea

Numerous studies have shown that the mere expectation improvement can alleviate symptoms in various conditions. These placebo effects often include reliable changes in central and peripheral organ systems. Here, we tested for the first time whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 healthy participants were exposed to a 20-min vection stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and gastric activity could be verified. Using state-of-the-art proteomics, 74 differentially regulated proteins were identified in placebo-treated participants as compared to no-treatment controls. Gene ontology (GO) enrichment analyses of these proteins revealed acute-phase proteins as well as microinflammatory proteins to be reliable plasma correlates of the placebo effect. Regression analyses showed that day-adjusted scores of nausea indices in the placebo group were predictable by the identified GO protein signatures. We next identified specific plasma proteins, for which a significant amount of variance could be explained by the experimental factors sex, group, nausea, or their interactions. GO enrichment analyses of these proteins identified grooming behavior as a prominent hit, based on neurexin-1 (NRXN1) and contactin-associated protein-like 4 (CNTNAP4). Finally, Receiver Operator Characteristics (ROC) allowed to identify specific plasma proteins differentiating placebo responders from non-responders. These comprised immunoglobulins (IGHM, IGKV1D-16, IGHV3-23, IGHG1) and MASP2, related to regulation of complement activation, as well as proteins involved in oxidation reduction processes (QSOX1, CP TXN). This proof-of-concept study indicates that plasma proteomics are a promising tool to identify molecular correlates and predictors of the placebo effect in humans.

neuroscience↗

bioRxiv2018

A cell-density dependent metabolic switch sensitizes breast cancer cells to ferroptosis

Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent phospholipid peroxidation. It can be induced by inhibiting glutathione peroxidase 4 (GPX4), the key enzyme for efficiently reducing peroxides within phospholipid bilayers. Recent data suggest that cancer cells undergoing EMT (dedifferentiation) and those resistant to standard therapy expose a high vulnerability toward ferroptosis. Although recent studies have begun to identify and characterize the metabolic and genetic determinants underlying ferroptosis, many mechanisms that dictate ferroptosis sensitivity remain unknown. Here, we show that low cell density sensitizes primary mammary epithelial and breast cancer cells to ferroptosis induced by GPX4 inhibition, whereas high cell density confers resistance. These effects occur irrespective of oncogenic signaling, cellular phenotype and expression of the fatty acid ligase acyl-CoA synthetase long chain family member 4 (ACSL4). By contrast, we show that a massive accumulation of neutral triacylglycerides (TAG) enriched with polyunsaturated fatty acids (PUFA) is induced at low cell density. In addition, de novo lipogenesis and desaturation pathways were found to be reduced at low cell density, indicative of increased fatty acid uptake. Our study suggests that PUFA-mediated toxicity is limited by the enrichment in TAGs that in turn might pose a vulnerability towards ferroptosis. Conclusively, cell density regulates lipid metabolism of breast epithelial and cancer cells, which results in a ferroptosis-sensitive cell state with the potential to be exploited therapeutically during metastatic dissemination.

cancer biology↗