Biology subjects

Delort, F.

Publications and source records attributed to Delort, F..

3 recordsLinked to original sources

bioRxiv2024

Mechanical constraints organize 3D tissues and orchestrate muscle differentiation

Biological tissues achieve proper shape and ordered structures during development through responses to internal and external signals, with mechanical cues playing a crucial role. These forces guide cellular organization, leading to complex self-organizing structures that are foundational to embryonic patterns. Emerging theories and experiments suggest that "topological morphogens" drive these processes. Despite the predominance of three-dimensional (3D) structures in biology, studying 3D tissues remains challenging due to limited model systems and the complexity of modeling. Here, we address these challenges by using self-organized cellular aggregates, specifically spindle-shaped C2C12 myoblasts, subjected to controlled mechanical stretching. Our findings reveal that these cells form a multilayered, actin-oriented tissue structure, where mechanical forces drive long-range 3D organization and muscle differentiation. Notably, tissue surface emerges as a hotspot for differentiation, correlating with directional order as shown by single molecule fluorescent in situ hybridization. Significance StatementWe explore how cells work together to form complex structures, particularly in 3D, using muscle precursors cells (C2C12 myoblasts) as a model. By applying controlled stretching forces, we found that these cells self-organize into layered tissues that guide their transformation into muscle. This research highlights the critical role of physical forces in shaping tissues, suggesting that the way cells are physically arranged and stretched in three dimensions can significantly influence their behavior and function. Our findings offer new insights into how tissues develop and could have implications for tissue engineering, where creating the right 3D environment is key to successful tissue growth and repair.

biophysics↗

bioRxiv2024

Integrated data from R405W desmin knock-in mice highlight alterations of mitochondrial function, protein quality control, and myofibrillar structure in the initial stages of myofibrillar myopathy

BackgroundMutations in the desmin gene cause skeletal myopathies and cardiomyopathies. The objective of this study was to elucidate the molecular pathology induced by the expression of R405W mutant desmin in murine skeletal muscle tissue. MethodsA comprehensive characterization of the skeletal muscle pathology in hetero- and homozygous R405W desmin knock-in mice was performed, employing grip strength, blood acylcarnitine and amino acid, histological, ultrastructural, immunofluorescence, immunoblot, ribosomal stalling, RNA sequencing and proteomic analyses. ResultsBoth hetero- and homozygous R405W desmin knock-in mice showed classical myopathological features of a myofibrillar myopathy with desmin-positive protein aggregation, degenerative changes of the myofibrillar apparatus, increased autophagic build-up, and mitochondrial alterations. Muscle weakness and increased blood concentrations of acylcarnitines and amino acids were only present in homozygous animals. During its translation, mutant desmin does not induce terminal ribosomal stalling. Analyses of RNA sequencing and proteomic data from soleus muscle of 3-month-old mice depicted 59 up- and 2 down-regulated mRNAs and 101 up- and 18 down-regulated proteins that were shared between the heterozygous and homozygous genotypes in the respective omics datasets compared to the wild-type genotype. Combined analysis of the omics data demonstrated 187 significantly dysregulated candidates distributed across four groups of regulation. A down-regulation on the mRNA and protein levels was observed for a multitude of mitochondrial proteins including essential proton gradient-dependent carriers. Up-regulation on both omics levels was present for the transcription factor Mlf1, which is a binding partner of protein quality control related Dnajb6. Down-regulated on mRNA but up-regulated on the protein level was the sarcomeric lesion marker Xirp2 (xin actin-binding repeat-containing protein 2), whereas Ces2c (acylcarnitine hydrolase) was regulated in the opposite way. ConclusionsThe present study demonstrates that the expression of mutant desmin results in a myofibrillar myopathy in hetero- and homozygous R405W desmin knock-in mice. Combined morphological, transcriptomic and proteomic analyses helped to decipher the complex pattern of early pathological changes induced by the expression of mutant desmin. Our findings highlight the importance of major mitochondrial alterations, including essential proton gradient-dependent carriers as well as Dnajb6-related protein quality control and Xin-related myofibrillar damage, in the molecular pathogenesis of desminopathies.

neuroscience↗

bioRxiv2021

Multiparameters dependance of tissue shape maintenance in myoblasts multicellular aggregates: the role of intermediate filaments.

Liquid and elastic behavior of tissues drives their morphology and their response to the environment. They appear as the first insight on tissue mechanics. We explore the role of individual cell properties on spheroids of mouse muscle precursor cells by developing a fully automated surface tension and Youngs modulus measurement system. Flattening multicellular aggregates under magnetic constraint, we show that rigidity and surface tension act as highly sensitive macroscopic reporters closely related to microscopic local tension and effective adhesion. Shedding light on the major contributions of acto-myosin contractility, actin organization and intercellular adhesions, we reveal the role of desmin organization on the macroscopic mechanics of this tissue model.

biophysics↗