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Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model

Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-dystroglycan (matriglycan) resulting from mutations of Fukutin-related protein (FKRP). There is no effective therapy currently available. We recently demonstrated that ribitol sup...

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Autores principales: Wu, Bo, Drains, Morgan, Shah, Sapana N., Lu, Pei Juan, Leroy, Victoria, Killilee, Jessalyn, Rawls, Raegan, Tucker, Jason D., Blaeser, Anthony, Lu, Qi Long
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714851/
https://www.ncbi.nlm.nih.gov/pubmed/36454905
http://dx.doi.org/10.1371/journal.pone.0278482
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author Wu, Bo
Drains, Morgan
Shah, Sapana N.
Lu, Pei Juan
Leroy, Victoria
Killilee, Jessalyn
Rawls, Raegan
Tucker, Jason D.
Blaeser, Anthony
Lu, Qi Long
author_facet Wu, Bo
Drains, Morgan
Shah, Sapana N.
Lu, Pei Juan
Leroy, Victoria
Killilee, Jessalyn
Rawls, Raegan
Tucker, Jason D.
Blaeser, Anthony
Lu, Qi Long
author_sort Wu, Bo
collection PubMed
description Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-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 in vitro and in FKRP-P448L (P448L) mutant mouse model through drinking water administration. To be clinically relevant, we have now conducted a dose-escalating efficacy study by gavage in P448L 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.
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spelling pubmed-97148512022-12-02 Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model Wu, Bo Drains, Morgan Shah, Sapana N. Lu, Pei Juan Leroy, Victoria Killilee, Jessalyn Rawls, Raegan Tucker, Jason D. Blaeser, Anthony Lu, Qi Long PLoS One Research Article Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-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 in vitro and in FKRP-P448L (P448L) mutant mouse model through drinking water administration. To be clinically relevant, we have now conducted a dose-escalating efficacy study by gavage in P448L 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. Public Library of Science 2022-12-01 /pmc/articles/PMC9714851/ /pubmed/36454905 http://dx.doi.org/10.1371/journal.pone.0278482 Text en © 2022 Wu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wu, Bo
Drains, Morgan
Shah, Sapana N.
Lu, Pei Juan
Leroy, Victoria
Killilee, Jessalyn
Rawls, Raegan
Tucker, Jason D.
Blaeser, Anthony
Lu, Qi Long
Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model
title Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model
title_full Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model
title_fullStr Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model
title_full_unstemmed Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model
title_short Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model
title_sort ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2i mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714851/
https://www.ncbi.nlm.nih.gov/pubmed/36454905
http://dx.doi.org/10.1371/journal.pone.0278482
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