{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T23:20:19Z","timestamp":1789255219833,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Becker muscular dystrophy (BMD) is a genetic neuromuscular disease of growing importance caused by in\u2010frame, partial loss\u2010of\u2010function mutations in the dystrophin (<jats:italic>DMD<\/jats:italic>) gene. BMD presents with reduced severity compared with Duchenne muscular dystrophy\u00a0(DMD), the allelic disorder of complete dystrophin deficiency. Significant therapeutic advancements have been made in DMD, including four FDA\u2010approved drugs. BMD, however, is understudied and underserved\u2014there are no drugs and few clinical trials. Discordance in therapeutic efforts is due in part to lack of a BMD mouse model which would enable greater understanding of disease and de\u2010risk potential therapeutics before first\u2010in\u2010human trials. Importantly, a BMD mouse model is becoming increasingly critical as emerging DMD dystrophin restoration therapies aim to convert a DMD genotype into a BMD phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We use CRISPR\/Cas9 technology to generate<jats:italic>bmx<\/jats:italic>(<jats:italic>B<\/jats:italic>ecker<jats:italic>m<\/jats:italic>uscular dystrophy,<jats:italic>X<\/jats:italic>\u2010linked) mice, which express an in\u2010frame ~40\u2009000\u00a0<jats:sc>bp<\/jats:sc>deletion of exons 45\u201347 in the murine<jats:italic>Dmd<\/jats:italic>gene, reproducing the most common BMD patient mutation. Here, we characterize muscle pathogenesis using molecular and histological techniques and then test skeletal muscle and cardiac function using muscle function assays and echocardiography.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Overall,<jats:italic>bmx<\/jats:italic>mice present with significant muscle weakness and heart dysfunction versus wild\u2010type (WT) mice, despite a substantial improvement in pathology over dystrophin\u2010null<jats:italic>mdx52<\/jats:italic>mice.<jats:italic>bmx<\/jats:italic>mice show impaired motor function in grip strength (\u221239%,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), wire hang (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0025), and<jats:italic>in vivo<\/jats:italic>as well as<jats:italic>ex vivo<\/jats:italic>force assays. In aged<jats:italic>bmx<\/jats:italic>, echocardiography reveals decreased heart function through reduced fractional shortening (\u221225%,<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0036). Additionally, muscle\u2010specific serum CK is increased &gt;60\u2010fold (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), indicating increased muscle damage. Histologically,<jats:italic>bmx<\/jats:italic>muscles display increased myofibre size variability (minimal Feret's diameter:<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0017) and centrally located nuclei indicating degeneration\/regeneration (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001).<jats:italic>bmx<\/jats:italic>muscles also display dystrophic pathology; however, levels of the following parameters are moderate in comparison with<jats:italic>mdx52<\/jats:italic>: inflammatory\/necrotic foci (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001), collagen deposition (+1.4\u2010fold,<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0217), and sarcolemmal damage measured by intracellular IgM (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0878). Like BMD patients,<jats:italic>bmx<\/jats:italic>muscles show reduced dystrophin protein levels (~20\u201350% of WT), whereas<jats:italic>Dmd<\/jats:italic>transcript levels are unchanged. At the molecular level,<jats:italic>bmx<\/jats:italic>muscles express increased levels of inflammatory genes, inflammatory miRNAs and fibrosis genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The<jats:italic>bmx<\/jats:italic>mouse recapitulates BMD disease phenotypes with histological, molecular and functional deficits. Importantly, it can inform both BMD pathology and DMD dystrophin restoration therapies. This novel model will enable further characterization of BMD disease progression, identification of biomarkers, identification of therapeutic targets and new preclinical drug studies aimed at developing therapies for BMD patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13171","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T08:47:25Z","timestamp":1673426845000},"page":"940-954","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The X\u2010linked Becker muscular dystrophy (<i>bmx<\/i>) mouse models Becker muscular dystrophy via deletion of murine dystrophin exons 45\u201347"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7914-2068","authenticated-orcid":false,"given":"Christopher R.","family":"Heier","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Hospital Washington DC 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Breanne L.","family":"Newell\u2010Stamper","sequence":"additional","affiliation":[{"name":"Edgewise Therapeutics, BioFrontiers Institute University of Colorado Boulder CO 80303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan J.","family":"Russell","sequence":"additional","affiliation":[{"name":"Edgewise Therapeutics, BioFrontiers Institute University of Colorado Boulder CO 80303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3458-8036","authenticated-orcid":false,"given":"Alyson A.","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine Research Children's National Hospital Washington DC USA"},{"name":"Department of Genomics and Precision Medicine George Washington University School of Medicine and Health Sciences Washington DC 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