Complementing Muscle Regeneration: Fibro-Adipogenic Progenitor and Macrophage-Mediated Repair of Elderly Human Skeletal Muscle

Complementing Muscle Regeneration: Fibro-Adipogenic Progenitor and Macrophage-Mediated Repair of Elderly Human Skeletal Muscle | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Complementing Muscle Regeneration: Fibro-Adipogenic Progenitor and Macrophage-Mediated Repair of Elderly Human Skeletal Muscle Jean Farup, Jonas Brorson, Lin Lin, Jakob Wang, Tine Billeskov, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4471420/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Jun, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The capacity to regenerate skeletal muscle function after injury requires a complex and well-coordinated cellular response, which is challenged in aged skeletal muscle. Here, we unravel the intricate dynamics of elderly human skeletal muscle regeneration by combining spatial, temporal, and single cell transcriptomics. Using spatial RNA sequencing, we profiled the expression of human protein-coding genes in elderly human skeletal muscle biopsies before as well as 2-, 8-, and 30-days post injury. Single Cell-Spatial deconvolution analysis highlights monocytes/macrophages and fibro-adipogenic progenitors (FAPs) as pivotal players in human muscle regeneration. By utilizing flow cytometry and cell sorting we confirmed increased cellular content and activity during regeneration. Spatial correlation analysis unveils FAPs and monocytes/macrophages co-localization and intercellular communication, mediated by complement factor C3. Immunostaining confirms C3 expression in FAPs and FAP secretion of C3, suggesting a role in phagocytosis of necrotic muscle cells. Finally, functional assays demonstrate C3's impact on human monocyte metabolism, survival and phagocytosis, unveiling its involvement in skeletal muscle regeneration. These insights elucidate FAP-macrophage interplay in aged human muscle with perspectives for future therapeutic interventions to reduce the aged induced decline in regenerative capacity. Biological sciences/Cell biology/Mechanisms of disease Biological sciences/Physiology/Ageing Biological sciences/Stem cells/Mesenchymal stem cells Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 05 Jun, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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