Drp1-FGF21 axis drives FAPs-mediated fibro-adipogenic degeneration in Duchenne muscular dystrophy

Drp1-FGF21 axis drives FAPs-mediated fibro-adipogenic degeneration in Duchenne muscular dystrophy | Research Square 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Article Drp1-FGF21 axis drives FAPs-mediated fibro-adipogenic degeneration in Duchenne muscular dystrophy Clara De Palma, Silvia Casati, Silvia Zecchini, Christel Gentil, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8926306/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Mitochondrial dysfunction is an early pathogenic event in dystrophic muscle contributing to muscle damage. Here, we provide an in-depth characterization of the marked induction of mitochondrial fission in mdx muscle fibers, driven by excessive activation of the fission regulator Drp1. This aberrant Drp1 activity triggers the integrated stress response (ISR), resulting in muscle-derived secretion of FGF21, which in turn promotes the fibro-adipogenic differentiation of fibro-adipogenic progenitors (FAPs). Importantly, we demonstrate that inhibition of Drp1 is both necessary and sufficient to restore mitochondrial function and suppresses FGF21 upregulation, limiting its detrimental impact on FAPs and contributing to the overall improvement of DMD phenotype. Our study identifies FGF21 as a key mediator of DMD pathology and supports targeting mitochondrial dynamics as a disease-modifying therapeutic strategy. Health sciences/Medical research/Preclinical research Health sciences/Diseases mitochondrial fission Drp1 FGF21 FAPs Duchenne muscular dystrophy fibro-adipogenic differentiation Full Text Additional Declarations There is no duality of interest Supplementary Files CasatietalSupplementaryMethods.pdf Supplementary methods Casatietal.supplementaryfiguresandtables.pdf Supplementary figures and tables Casatietal.supplementaryfilesuncroppedWB.pdf Supplementary figure - uncropped WB Cite Share Download PDF Status: Under Review 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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