Biology subjects

Weiss-Gayet, M.

Publications and source records attributed to Weiss-Gayet, M..

4 recordsLinked to original sources

bioRxiv2025

Defective plasticity in dermatomyositis patients muscle stem cells is associated with sustained intrinsic inflammatory signaling and disruption of the histone H3.3 chromatin loading pathway

Skeletal muscle regeneration is driven by muscle stem cells (MuSCs), which proliferate, differentiate and fuse to reform myofibers and restore muscle function. This myogenesis process is driven both by intrinsic MuSC properties and extrinsic cues. While coordinated inflammatory signals are necessary for healthy regeneration, chronic inflammation participates in various pathologies affecting the skeletal muscle. In the idiopathic inflammatory myopathy dermatomyositis (DM), MuSCs exhibit impaired myogenesis in vitro, indicating that they may have acquired intrinsic defects, contributing to the disease and providing a mechanism for sustained patient muscle weakness despite efficient anti-inflammatory treatments. Here, we investigated the transcriptomic regulation of DM-derived MuSCs, with a focus on the H3.3 histone variant which regulates myogenesis progression. DM-derived MuSCs were unable to effectively execute the myogenic transcriptional program during in vitro differentiation. They exhibited an activated canonical TNF- signaling. They also showed reduced expression of H3.3 and its chaperone genes, coupled with a decrease in H3.3 deposition across the entire genome, and particularly at myogenic regulatory factor loci. The loss of H3.3 combined with elevated TNF- signaling was associated with a failure of DM-derived MuSCs to achieve myogenesis, suggesting a mechanistic link between epigenetic dysregulation and defective muscle regeneration in humans.

molecular biology↗

bioRxiv2024

Macrophage-derived RNAseT2 stimulates muscle stem cell fusion via SLK/N-WASP/actin bundling

Muscle stem cells (MuSCs) fuse to form myofibers to repair skeletal muscle after injury. Within the regenerative MuSC niche, restorative macrophages stimulate MuSC fusion, although the molecular mechanisms involved are largely unknown. Here, we show that restorative macrophages secrete ribonuclease T2 (RNAseT2) to stimulate MuSC fusion. RNAseT2 entered MuSCs via the mannose receptor and induced the formation of actin bundles in MuSCs, enabling cell/cell fusion. Mechanistically, RNAseT2 bound to Ste20-like kinase (SLK), which itself triggered the phosphorylation-mediated activation of N-WASP, through Paxillin phosphorylation, allowing actin bundling necessary for MuSC fusion. In vivo, overexpressing RNAseT2 in regenerating muscle increased fusion in newly formed myofibers in mouse and zebrafish while macrophages deficient for RNAseT2 gene led to fusion defect and smaller myofibers. This study reveals a new function for the highly conserved RNAseT2 and provides a new molecular mechanism by which restorative macrophages support MuSC fusion during muscle repair.

cell biology↗

bioRxiv2023

Epigenetic control of myogenic identity of human muscle stem cells in Duchenne Muscular Dystrophy

In Duchenne Muscular Dystrophy (DMD), the absence of the subsarcolemmal dystrophin protein leads to repeated myofiber damages inducing cycles of muscle regeneration that is driven by muscle stem cells (MuSCs). With time, MuSC regenerative capacities are overwhelmed, leading to fibrosis and muscle atrophy. Whether MuSCs from DMD muscle have intrinsic defects that limit regenerative potential or are disrupted by their degenerative/regenerative environment is unclear. We investigated cell behavior and gene expression in human using MuSCs derived from DMD or healthy muscles. We found that proliferation, differentiation and fusion were not altered in DMD-MuSCs, but with time, they lost their myogenic identity twice as fast as healthy MuSCs. The rapid drift towards a fibroblast-like cell identity was observed at the clonal level, and resulted from the altered expression of epigenetic enzymes required to maintain the myogenic cell fate. Indeed, the re-expression of CBX3, SMC3, H2AFV and H3F3B prevented the MuSC identity drift. Amongst the epigenetic changes, a closing of chromatin at the gene encoding the transcription factor MEF2B caused a down-regulation of its expression and a loss of the myogenic fate. Thus, MEF2B is a key mediator of the myogenic identity in human MuSCs, that is altered in DMD pathology.

genomics↗

bioRxiv2023

Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD

Lack of dystrophin is the genetic basis for the Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2-mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2-mdx muscles is associated with enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports excessive accumulation of fibroadipogenic progenitors (FAPs). Unexpectedly, the extent of damage and degeneration of juvenile D2-mdx muscle is reduced in adults and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance myogenesis in the adult D2-mdx muscle, reaching levels comparable to the milder (B10-mdx) mouse model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with the juvenile D2-mdx FAPs reduced their fusion efficacy and in vivo glucocorticoid treatment of juvenile D2 mouse improved muscle regeneration. Our findings indicate that aberrant stromal cell response contributes to poor myogenesis and greater muscle degeneration in dystrophic juvenile D2-mdx muscles and reversal of this reduces pathology in adult D2-mdx mouse muscle, identifying these as therapeutic targets to treat dystrophic DMD muscles.

pathology↗