Biology subjects

Dumitru, A. C.

Publications and source records attributed to Dumitru, A. C..

3 recordsLinked to original sources

bioRxiv2026

Methylglyoxal-derived glycation tunes nuclear viscoelasticity

Reactive carbonyl metabolites such as methylglyoxal (MGO) accumulate in diabetes, aging, and metabolic disease, conditions frequently associated with pathological stiffening of human cells and tissues. While glycation of extracellular matrices and cytoskeletal proteins is known to contribute to these mechanical changes, whether the nucleus itself is a direct mechanical target of carbonyl stress remains unknown. Here, by combining advanced atomic force microscopy-based nanomechanical probing with correlative confocal imaging, we show that MGO-derived glycation directly remodels isolated cell nuclei, increasing stiffness, reducing fluidity, and restricting intranuclear deformation propagation. MGO-derived adducts accumulate prominently at the nuclear envelope, and perturbation of lamin A/C and chromatin state reveals that both structures contribute to glycation-induced stiffening. In cells, chronic MGO exposure induces nucleus-intrinsic stiffening and biases YAP nuclear localization in a substrate-stiffness-dependent manner, linking nuclear glycation to altered mechanosensitive regulation. In vivo, cardiac nuclear stiffening is only observed along with increased immunodetected MGO-adduct burden, while nuclear fluidity remains largely preserved. Together, these findings establish nonenzymatic glycation as a metabolic mechanism that remodels nuclear mechanics and alters cellular mechanosensing, revealing a previously unrecognized physical consequence of carbonyl stress.

biophysics↗

bioRxiv2026

Pathological stiffening by crosslinking glycation of titin

Heterogeneous, non-enzymatic glycation chemistry triggered by sugar-derived metabolites is typical of diseases that also entail pathological stiffening of cells, such as diabetes and age-related disorders. However, the mechanisms responsible for cell stiffening and the role of glycated biomolecules remain largely unexplored. Here, we show that glycation of cardiac titin, a giant intracellular protein scaffolding contractile sarcomeres, is increased in diabetes and leads to rigidification of both the protein and cardiomyocytes. Mechanistically, glycation-induced titin stiffening results from decreased contour length and enhanced folding of otherwise structurally intact protein domains following extensive formation of intramolecular crosslinking advanced glycation end products (AGEs). These stiffening effects outweigh softening contributions by competing, non-crosslinking AGEs. In combination, our work overcomes the intrinsic chemical complexity typical of glycation to uncover crosslinking AGEs as a source of pathological stiffening of cells, which we propose contributes to tissue dysfunction in situations of glycative stress.

biophysics↗

bioRxiv2025

Titin cleavage in living cardiomyocytes induces sarcomere disassembly but does not trigger cell proliferation

AimsAdult mammalian hearts have limited regenerative capacity due to the inability of cardiomyocytes to proliferate, a major clinical hurdle in contemporary cardiology. The presence of highly organized, contractile sarcomeres has long been considered an impediment for cardiomyocyte division. Indeed, sarcomere disassembly is a crucial step to complete the cell cycle in the few situations where cardiomyocytes have been observed to proliferate. However, whether sarcomere disassembly can per se trigger cell cycle re-entry remains unknown, a possibility that we have tested here. Methods and resultsWe have engineered a system to induce sarcomere disassembly in living murine cardiomyocytes based on the specific cleavage of the structural protein titin by tobacco etch virus protease (TEVp). Although isolated neonatal cardiomyocytes with disassembled sarcomeres remain viable and retain low-amplitude contractile activity, our results show no evidence of increased cardiomyocyte proliferation in targeted cells, as indicated by analyses of markers of DNA synthesis and cytokinesis. We obtain equivalent results when titin is cleaved in the adult myocardium in vivo. ConclusionThe removal of sarcomere structural barriers is necessary, but not sufficient, for cardiomyocyte proliferation, which implies that additional factors are required for cardiomyocytes to undergo cell division. Translational perspectiveThere is a clinical need to identify therapeutic strategies that promote cardiac regeneration through the proliferation of cardiomyocytes that survive an injury to the heart, for instance after myocardial infarction. Based on the observation that cardiomyocytes require sarcomere disassembly for proliferation, we have examined if the sole disassembly of sarcomeres is enough to promote cell division in cardiomyocytes. Our work demonstrates a strategy to induce specific sarcomere disassembly, which, however does not result in increased proliferative capacity of cardiomyocytes. These results imply that additional factors need to be considered to promote cardiomyocyte proliferation by facilitating sarcomere disassembly.

cell biology↗