Biology subjects

Allamand, V.

Publications and source records attributed to Allamand, V..

4 recordsLinked to original sources

bioRxiv2025

Collagen VI is a conserved pro-fibrotic signal disrupting muscle regeneration across distinct human myopathies

Muscle fibrosis is a major driver of progression in diverse myopathies, yet the conserved molecular mediators of this process in humans remains poorly defined. Here, we identify collagen VI as a common pro-fibrotic and regeneration-impairing extracellular matrix (ECM) component across three distinct human myopathies: Duchenne Muscular Dystrophy (DMD), Oculopharyngeal Muscular Dystrophy (OPMD), and Inclusion Body Myositis (IBM). Proteomic profiling of fibrotic biopsies revealed consistent upregulation of collagen VI and laminin {gamma}1, alongside disease-specific alterations involving other ECM proteins. Fibro-adipogenic progenitors (FAPs) are the predominant source of these ECM components, including collagen VI and laminin {gamma}1. Functionally, xenotransplantation of patient-derived FAPs into regenerating mouse muscle induced localized collagen deposition, myofiber atrophy, and depletion of Pax7 muscle stem cells. Mechanistic assays demonstrated that FAP-derived collagen VI is sufficient to impair myogenic fusion, while silencing COL6 in patient FAPs restores fusion capacity, directly linking pathological collagen VI deposition to regeneration failure. Our findings uncover collagen VI as a conserved effector of fibrosis and stem cell niche disruption in human myopathies, positioning it as a potential therapeutic target across genetically and clinically distinct muscle diseases.

cell biology↗

bioRxiv2025

Generation and Characterization of Col6a1 knock-in mice: A Promising Pre-Clinical Model for Collagen VI-Related Dystrophies

Collagen VI Related Dystrophies (COL6-RD) are congenital muscle diseases, typically inherited as an autosomal dominant trait. A frequent type of mutation involves glycine substitutions in the triple helical domain of collagen VI alpha chains, exerting a dominant-negative effect on the unaltered protein. Despite this, no prior animal model captured this mutation type. Using CRISPR/Cas9, we generated transgenic mice with the equivalent of the human COL6A1 c.877 G>A; p. Gly293Arg mutation. We characterized their skeletal muscle phenotype over time, utilizing computer-aided tools applied to standardized parameters of muscle pathology and function. Knock-in mice exhibited early-onset reduced muscle weight, myopathic histology, increased fibrosis, reduced collagen VI expression, muscle weakness, and impaired respiratory function. These features provide adequate outcome measures to assess therapeutic interventions. The different automated image analysis methods deployed here analyze thousands of features simultaneously, enhancing accuracy in describing muscle disease models. Overall, the Col6a1 Ki Gly292Arg mouse model offers a robust platform to deepen our understanding of COL6-RD and advance its therapeutic landscape. Summary StatementWe generated and characterized over time the first mouse model representing dominant negative glycine substitutions in the alpha chains of collagen VI that are a frequent cause of Collagen VI-Related Dystrophies.

neuroscience↗

bioRxiv2023

Alterations of the TGFb-sequestration complex member ADAMTSL1 levels are associated with muscular defects and rhabdomyosarcoma aggressiveness

Rhabdomyosarcoma (RMS) is the most frequent form of paediatric soft-tissue sarcoma and remains a medical challenge, holding in failure current therapeutic strategies. RMS shares histological features with cells of the muscle lineage and this cancer is thought to arise from malignant transformation of myogenic precursors. It has been proposed that RMS and myogenesis could represent the "Jekyll and Hyde" of skeletal muscle. The underlying idea is that some early steps of myogenic differentiation are blocked in RMS, and that understanding how the normal process has gone awry could help to decipher the biological underpinnings of tumorigenesis and tumor escape. It is widely agreed that extracellular matrix (ECM) interferes in skeletal muscle regeneration and that defects in ECM components are clinically significant. The challenge is now to decipher actors and mechanisms responsible for the transmission of signals to muscle cells and the subsequent alterations that could be associated with RMS. Using an original transgenic mice model, we show here that ADAMTSL1 is involved in skeletal muscle regeneration. As previously reported for other members of its family, ADAMTSL1 is part of the TGF-{beta}-ECM-sequestering complex and likely positively regulates TGF-{beta}-pathway activity. Last, we observed that ADAMTSL1 expression behaves as a strong prognostic factor in the aggressive fusion-positive RMS and correlates with a neural-like phenotype of tumor cells, resulting from gain of SMAD2/3/4 targets.

cancer biology↗

bioRxiv2022

Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington's disease

Huntingtons disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

pathology↗