COLAS, A. | bioRxiv Science

bioRxiv2024

Tenascin-C from the tissue microenvironment promotes muscle stem cell self-renewal through Annexin A2

Skeletal muscle tissue self-repair occurs through the finely timed activation of resident muscle stem cells (MuSC). Following perturbation, MuSC exit quiescence, undergo myogenic commitment, and differentiate to regenerate the injured muscle. This process is coordinated by signals present in the tissue microenvironment, however the precise mechanisms by which the microenvironment regulates MuSC activation are still poorly understood. Here, we identified Tenascin-C (TnC), an extracellular matrix (ECM) glycoprotein, as a key player in promoting of MuSC self-renewal and function. We show that fibro-adipogenic progenitors (FAPs) are the primary cellular source of TnC during muscle repair, and that MuSC sense TnC signaling through cell the surface receptor Annexin A2. We provide in vivo evidence that TnC is required for efficient muscle repair, as mice lacking TnC exhibit a regeneration phenotype of premature aging. We propose that the decline of TnC in physiological aging contributes to inefficient muscle regeneration in aged muscle. Taken together, our results highlight the pivotal role of TnC signaling during muscle repair in healthy and aging skeletal muscle.

cell biology↗

bioRxiv2021

Genetic architecture of natural variations of cardiac performance in flies

Deciphering the genetic architecture of human cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. We investigated the natural variation of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP). Genome Wide Associations Studies (GWAS) identified genetic networks associated with natural variation of cardiac traits which were used to gain insights as to the molecular and cellular processes affected. Non-coding variants that we identified were used to map potential regulatory non-coding regions, which in turn were employed to predict Transcription Factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were also validated by heart specific knockdown. Additionally, we showed that the natural variations associated with variability in cardiac performance affect a set of genes overlapping those associated with average traits but through different variants in the same genes. Furthermore, we showed that phenotypic variability was also associated with natural variation of gene regulatory networks. More importantly, we documented correlations between genes associated with cardiac phenotypes in both flies and humans, which supports a conserved genetic architecture regulating adult cardiac function from arthropods to mammals. Specifically, roles for PAX9 and EGR2 in the regulation of the cardiac rhythm were established in both models, illustrating that the characteristics of natural variations in cardiac function identified in Drosophila can accelerate discovery in humans.

genetics↗