Biology subjects

Clemente-Manteca, A.

Publications and source records attributed to Clemente-Manteca, A..

3 recordsLinked to original sources

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 is a driver of cardiomyocyte disengagement and reactive myocardial fibrosis

Myocardial remodeling including cardiomyocyte-death-independent, reactive fibrosis and disconnection of cardiomyocytes is at the basis of prevalent cardiac conditions converging into arrhythmias and heart failure. However, the molecular mechanisms behind these pathogenic responses remain incompletely understood limiting therapeutic opportunities. Here, we find that a molecular event common to unrelated heart diseases, namely the cleavage of the sarcomeric protein titin, is enough to trigger fast myocardial remodeling. Using an engineered system based on the expression of tobacco etch virus protease (TEVp) in mice, we show that 30% mosaic cardiac titin cleavage leads to global cardiomyocyte disengagement, activation of cardiac fibroblasts and interstitial collagen deposition. These effects are concurrent, involve ERK1/2 signaling, and are expected to contribute, at least, to myocardial remodeling in chemotherapy-induced cardiotoxicity and ischemia damage.

physiology↗

bioRxiv2022

Cell response to extracellular matrix energy dissipation outweighs rigidity sensing

The mechanical properties of the extracellular matrix (ECM) determine cell differentiation, proliferation and migration through mechanoresponsive proteins including YAP. However, how different mechanical signals cooperate, synergize or compete to steer cell behavior remains poorly understood. Here, we have examined competition between the two major ECM mechanical cues, i.e. rigidity, which activates cell mechanosensing, and viscous energy dissipation, which reduces stiffness blunting cell mechanotransduction. To trigger competition, we have engineered protein hydrogels allowing concomitant modulation of stiffness and viscosity by mechanisms characteristic of native ECM. Culturing cells on these hydrogels, we have found that substrate energy dissipation attenuates YAP mechanosensing prevailing over stiffness cues. Hampered YAP activation on more dissipative substrates correlates with faster actin flow and smaller focal adhesions. Mechanistically, inhibition of actomyosin contractility reverses the outcome of the competition between rigidity and energy dissipation. Our results highlight the dominating contribution of substrate viscosity to the biology of the cell.

bioengineering↗