Intracellular Membrane Repair Dysregulation and Accumulation of Mature Myostatin Protein are Novel Markers of Muscle Pathophysiology in Pompe Disease

Intracellular Membrane Repair Dysregulation and Accumulation of Mature Myostatin Protein are Novel Markers of Muscle Pathophysiology in Pompe Disease | 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 Research Article Intracellular Membrane Repair Dysregulation and Accumulation of Mature Myostatin Protein are Novel Markers of Muscle Pathophysiology in Pompe Disease Candice BABARIT, Sabrina JAGOT, Cindy SCHLEDER, Johan DENIAUD, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8603735/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase deficiency, characterized by progressive skeletal muscle weakness and respiratory insufficiency. Affected muscles exhibit glycogen-filled lysosomes, autophagic build-up, and mitochondrial abnormalities. Despite global myofibrillar disorganization, satellite cells (SCs) fail to activate, due to mechanisms that remain unclear. This study sought to comprehensively characterize the phenotypic features of affected muscles in Pompe disease, focusing in particular on membrane repair processes, as membrane damage is a primary trigger for SC activation. Longitudinal transcriptomic analysis of muscle from a Pompe disease mouse model, combined with immunohistochemical and biochemical analyses, showed early and sustained overexpression of dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2, proteins involved in membrane repair. Abnormal localization of these proteins was observed throughout the disease course, as evidenced by sarcoplasmic accumulation at lysosomes, autophagosomes, and T-tubules, respectively. These alterations suggest a compensatory mechanism to preserve the integrity of intracellular structures. Analysis of muscle biopsies from patients with late-onset Pompe disease (LOPD) suggested sarcoplasmic localization of DYSF, ANXA2 and AHNAK2 that correlated with the severity of the histological phenotype. Moreover, in the mouse model, we observed persistent post-transcriptional accumulation of mature myostatin, a key negative regulator of muscle growth, which may contribute to impaired SC activation and the absence of muscle regeneration despite extensive tissue damage. In conclusion, our findings identified differential expression of proteins associated with intracellular membrane repair and dysregulation of myostatin as key markers in the course of Pompe disease. These insights provide new perspectives on the underlying pathophysiology and point to novel therapeutic avenues for limiting disease-associated damage. Pompe disease skeletal muscle membrane repair satellite cell lysosome autophagosome T-tubule myostatin Full Text Additional Declarations No competing interests reported. Supplementary Files Additionalfile3.xls Additionalfile4.xls Additionalfile5.xls Additionalfile6.xls Additionalfile7.xls Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 Mar, 2026 Reviews received at journal 24 Feb, 2026 Reviews received at journal 19 Feb, 2026 Reviewers agreed at journal 12 Feb, 2026 Reviewers agreed at journal 29 Jan, 2026 Reviewers agreed at journal 27 Jan, 2026 Reviewers invited by journal 27 Jan, 2026 Editor assigned by journal 14 Jan, 2026 Submission checks completed at journal 14 Jan, 2026 First submitted to journal 14 Jan, 2026 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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 {"props":{"pageProps":{"initialData":{"identity":"rs-8603735","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":581382516,"identity":"41cf3226-7a96-46a8-848a-013efefccfe6","order_by":0,"name":"Candice BABARIT","email":"","orcid":"","institution":"Oniris, INRAE, PAnTher","correspondingAuthor":false,"prefix":"","firstName":"Candice","middleName":"","lastName":"BABARIT","suffix":""},{"id":581382517,"identity":"3d1f3e99-479d-4230-a9f2-122c374bee4e","order_by":1,"name":"Sabrina JAGOT","email":"","orcid":"","institution":"Oniris, INRAE, 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