{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T14:19:42Z","timestamp":1765808382954,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T00:00:00Z","timestamp":1719360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle predominantly drives the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). We recently demonstrated that berberine, an herbal extract known for its ability to stabilize guanine\u2013quadruplex structures, effectively downregulates DUX4 expression in FSHD patient-derived myoblasts and in mice overexpressing exogenous DUX4 after viral vector-based treatment. Here, we sought to confirm berberine\u2019s inhibitory efficacy on DUX4 in the widely used FSHD-like transgenic mouse model, ACTA1-MCM\/FLExDUX4, where DUX4 is induced at pathogenic levels using tamoxifen. Animals repeatedly treated with berberine via intraperitoneal injections for 4 weeks exhibited significant reductions in both mRNA and protein levels of DUX4, and in mRNA expression of murine DUX4-related genes. This inhibition translated into improved forelimb muscle strength and positive alterations in important FSHD-relevant cellular pathways, although its impact on muscle mass and histopathology was less pronounced. Collectively, our data confirm the efficacy of berberine in downregulating DUX4 expression in the most relevant FSHD mouse model. However, further optimization of dosing regimens and new studies to enhance the bioavailability of berberine in skeletal muscle are warranted to fully leverage its therapeutic potential for FSHD treatment.<\/jats:p>","DOI":"10.3390\/ijms25136994","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T05:11:39Z","timestamp":1719465099000},"page":"6994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Systemic Pharmacotherapeutic Treatment of the ACTA1-MCM\/FLExDUX4 Preclinical Mouse Model of FSHD"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7241-9607","authenticated-orcid":false,"given":"Ngoc","family":"Lu-Nguyen","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart","family":"Snowden","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Popplewell","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK"},{"name":"National Horizons Centre, Teesside University, Darlington DL1 1HG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0536-5231","authenticated-orcid":false,"given":"Alberto","family":"Malerba","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1097\/WCO.0b013e328357f22d","article-title":"Facioscapulohumeral Muscular Dystrophy: Consequences of Chromatin Relaxation","volume":"25","author":"Miller","year":"2012","journal-title":"Curr. 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