{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:14:09Z","timestamp":1786515249327,"version":"build-2736575974"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008156","name":"Carolinas HealthCare Foundation","doi-asserted-by":"publisher","award":["McColl-11"],"award-info":[{"award-number":["McColl-11"]}],"id":[{"id":"10.13039\/100008156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of \u03b1-dystroglycan (matriglycan) resulting from mutations of Fukutin-related protein (FKRP). There is no effective therapy currently available. We recently demonstrated that ribitol supplement increases levels of matriglycan in cells <jats:italic>in vitro<\/jats:italic> and in FKRP-P448L (<jats:italic>P448L<\/jats:italic>) mutant mouse model through drinking water administration. To be clinically relevant, we have now conducted a dose-escalating efficacy study by gavage in <jats:italic>P448L<\/jats:italic> mutant mice. Six months of ribitol treatment daily significantly rescued functions of skeletal, respiratory, and cardiac muscles dose-dependently. This was associated with a dose dependent increase in matriglycan and improvement in muscle pathology with reductions in muscle degeneration, inflammatory infiltration and fibrosis. Importantly, ribitol significantly increased life span and muscle functions of the female animals receiving treatment from 10 months of age. The only observed side effect was gastrointestinal tract bloating with loose stool and this effect is also dose dependent. The results validate the mechanism that ribitol as a pre-substrate of glycosyltransferase is able to compensate for the decreased function of mutant FKRP with restoration of matriglycan expression and provide a guidance for future clinical trial design.<\/jats:p>","DOI":"10.1371\/journal.pone.0278482","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T19:55:46Z","timestamp":1669924546000},"page":"e0278482","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model"],"prefix":"10.1371","volume":"17","author":[{"given":"Bo","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Drains","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sapana N.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei Juan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Leroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessalyn","family":"Killilee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8516-9590","authenticated-orcid":true,"given":"Raegan","family":"Rawls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6558-7808","authenticated-orcid":true,"given":"Jason D.","family":"Tucker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Blaeser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6969-0121","authenticated-orcid":true,"given":"Qi Long","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"pone.0278482.ref001","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1086\/324412","article-title":"Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystoglycan","volume":"69","author":"M Brockington","year":"2001","journal-title":"Am J Hum Genet"},{"key":"pone.0278482.ref002","doi-asserted-by":"crossref","first-page":"e61","DOI":"10.1136\/jmg.2003.013870","article-title":"Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome","volume":"41","author":"D Beltran-Valero de Bernab\u00e9","year":"2004","journal-title":"J Med Genet"},{"key":"pone.0278482.ref003","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nature00837","article-title":"Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies","volume":"418","author":"DE Michele","year":"2002","journal-title":"Nature"},{"key":"pone.0278482.ref004","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1093\/hmg\/10.25.2851","article-title":"Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C","volume":"10","author":"M Brockington","year":"2001","journal-title":"Hum Mol Genet"},{"key":"pone.0278482.ref005","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/S0002-9440(10)63160-4","article-title":"Abnormalities in alpha-dystroglycan expression in MDC1C and LGMD2I muscular dystrophies","volume":"164","author":"SC Brown","year":"2004","journal-title":"Am J Pathol"},{"key":"pone.0278482.ref006","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.ajpath.2016.02.015","article-title":"Glucocorticoid steroid and alendronate treatment alleviates dystrophic phenotype with enhanced functional glycosylation of alpha-dystroglycan in mouse model of Limb-Girdle Muscular Dystrophy with FKRPP448L mutation","volume":"186","author":"B Wu","year":"2016","journal-title":"Am J Pathol"},{"key":"pone.0278482.ref007","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.omtm.2017.02.002","article-title":"Efficacy of gene therapy Is dependent on disease progression in dystrophic mice with mutations in the FKRP gene","volume":"5","author":"CH Vannoy","year":"2017","journal-title":"Mol Ther. 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